About CMT2C
TRPV4 variants: what is known, what is uncertain, and how that changes
At a glanceEvery TRPV4 variant is classified as pathogenic, likely pathogenic, of uncertain significance (VUS), likely benign or benign. That label reflects the evidence available today, and it can change. A VUS neither confirms nor rules out a genetic cause, and your symptoms deserve care either way. About half of all TRPV4 variants in ClinVar are VUS [217].
Reading a TRPV4 result
Genetic reports describe the same change in several ways. Using my own variant as the example, a report might say:
TRPV4 · NM_021625.5 · c.557G>A · p.Arg186Gln · heterozygous
- TRPV4
- The gene.
- NM_021625.5
- The reference transcript, the “map” of the gene the lab used (version 5). It is the standard transcript for TRPV4, so positions from different labs normally line up [225].
- c.557G>A
- The DNA change: at position 557 of the coding sequence, the letter G is replaced by A.
- p.Arg186Gln
- The protein change: at position 186, the amino acid arginine (Arg) is replaced by glutamine (Gln). The short form, often used in papers, is R186Q. Parentheses, as in p.(Arg186Gln), mean the protein change is predicted from the DNA rather than measured [225].
- Heterozygous
- The change is in one of your two copies of the gene. TRPV4 neuromuscular disease is autosomal dominant, so one changed copy is enough to cause it [6].
When you look up a variant, search for both forms, for example “R186Q TRPV4” and “Arg186Gln TRPV4”. Older papers sometimes used older transcript versions, but the protein position is usually the same.
The five classifications
Since 2015, labs have used a shared five-tier system from the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) [205]. A lab weighs every piece of evidence for and against a variant causing disease, then picks one of five labels.
| Classification | Rough certainty | What it means for you |
|---|---|---|
| Pathogenic | More than 99% likely to cause disease [206] | The variant is accepted as the cause of the condition. |
| Likely pathogenic | More than 90% likely [205] | Treated as disease-causing in practice, together with the clinical picture. |
| Uncertain significance (VUS) | Somewhere between about 10% and 90% [207] | Not enough evidence, or evidence pointing both ways. It does not confirm or rule out a genetic cause. |
| Likely benign | More than 90% likely to be harmless [205] | Very probably not the cause. |
| Benign | More than 99.9% likely to be harmless [206] | Not the cause. Usually not listed on reports. |
The 90% line for “likely” is an agreed convention; the 2015 authors called it “common, albeit arbitrary”. “Uncertain” is the default whenever the rules for the other four are not met, or contradict each other [205].
What a VUS means, and what it does not
It is a statement about evidence, not about you
A variant either does or does not contribute to disease; that is a fact of biology. “Uncertain significance” only says that, today, there is not enough published or shared evidence to decide. The guidelines say a VUS “should not be used in clinical decision-making” and that “efforts to resolve the classification ... should be undertaken” [205]. UK guidance adds that reports should say the result “does not exclude a genetic diagnosis” [207].
Can you have symptoms from a VUS? Yes, it is possible
Every variant now accepted as pathogenic was once new and unclassified. Some VUS are later upgraded, once more people with the same change are found, relatives are tested or lab studies are done. In the largest study across many specialties, including neurology, about 1 in 5 reclassified VUS moved up to likely pathogenic or pathogenic [210]. When that happens, the research has caught up with what the person was already living with.
The honest other half
In large datasets, most VUS that get reclassified move down, to likely benign or benign: about 80 to 91% of them [210]. That does not mean the symptoms were imagined. It means the cause may lie elsewhere: another gene, a change the test could not detect, or a non-genetic cause.
A 2025 TRPV4 study shows why this matters. Among people whose TRPV4 variants turned out to behave normally in the lab, one had chronic inflammatory demyelinating polyneuropathy (CIDP), an immune condition that can be treated. In one family, the variant was carried by an unaffected sister but not by her brother, who had the neuropathy [22]. Keeping an open mind about a VUS protects you from missing a cause that has a treatment.
What this means in practice
- Your symptoms deserve care now. A neuropathy is diagnosed from your examination, family history and nerve tests (nerve conduction studies and EMG); genetics confirms the subtype [231]. Bracing, therapy and checks of breathing, voice and swallowing follow your symptoms, not the label on your report. The guidelines suggest that while a VUS is being looked into, “additional monitoring of the patient for the disorder in question may be prudent” [205].
- Relatives are not tested to predict their own health from a VUS [208]. They may be invited for testing, with their results used as evidence to help classify the variant.
- Research studies set their own genetic criteria. Ask a study team directly whether a VUS qualifies you. Registries and natural history studies often welcome people whose genetic diagnosis is still unresolved.
- Not every VUS is equally uncertain. A 2026 ACMG statement encourages labs to say whether a VUS leans toward benign (“VUS-low”) or deserves more follow-up (“VUS-high”) [227]. If your report doesn't say, ask the lab or your genetic counselor which way the evidence leans.
How reclassification works
Reclassification means a lab re-reviews a variant and changes its label because the evidence has changed. It can go in either direction, up or down. Less often, a pathogenic label is softened to likely pathogenic.
Who classifies variants
- Each testing lab classifies variants itself, using the shared ACMG/AMP rules. Two labs can disagree about the same variant.
- ClinVar, a free public database run by the US National Library of Medicine, collects these classifications. It shows an overall result and a star rating for how well reviewed that result is [217].
- Expert panels from ClinGen (the Clinical Genome Resource) can issue reviewed classifications that carry the most weight. No expert panel currently covers TRPV4 variants. ClinGen has rated the link between the TRPV4 gene and neuromuscular disease as “Definitive”, its highest level [216]. So the gene’s link to the disease is settled, but individual variants are judged one by one by labs.
The evidence that moves a variant
The rules group evidence into types. Most can count for or against a variant, and each has a code that labs use on reports [205].
| Evidence | Moves it toward pathogenic when... | Moves it toward benign when... |
|---|---|---|
| Population databasesPM2, BS1, BA1 | The variant is absent or extremely rare in large databases of the general population such as gnomAD [205]. | It turns up in healthy people too often to cause a rare disease. Large population databases have moved many VUS to benign [205]. |
| New in the patient (de novo)PS2, PM6 | Neither parent carries it and the person is affected. This is strong evidence when both parents are tested and parentage is confirmed. It was the most powerful reason for upgrades in a study of over 500,000 VUS [210]. | Not used in this direction. |
| Follows the condition in a family (segregation)PP1, BS4 | Affected relatives carry it. More informative relatives give stronger evidence: within one family, 3, 4 and 5 informative meioses (parent-to-child transmissions of the variant that can be checked) count as supporting, moderate and strong [229]. | An affected relative does not carry it. This needs care in TRPV4 disease, because some carriers have very mild or no symptoms [6]. |
| Lab experiments (functional studies)PS3, BS3 | A validated test shows that the variant changes the protein in the way that causes the disease. For TRPV4 neuropathy that means gain of function: an overactive channel [22]. | The same validated test shows the protein behaves normally. |
| Other patientsPS4, PP4, BP5 | More unrelated people with the same condition are found with the variant, or the person's features are very specific to TRPV4 disease. | The person already has a different confirmed genetic explanation. |
| Location in the proteinPM1, PM5, PS1 | It sits in a known hotspot (for TRPV4 neuropathy, the arginines on the ankyrin repeat domain), or another change at the same position is already known to be pathogenic [6]. | Mostly used in the pathogenic direction. |
| Computer predictionsPP3, BP4 | Several calibrated prediction tools agree it is damaging. | They agree it is harmless. If tools disagree, this evidence is not used [205]. |
A points system makes the logic clearer
A refinement of the rules turns each piece of evidence into points: supporting = 1, moderate = 2, strong = 4 and very strong = 8, with negative points for benign evidence. The totals map onto the five labels [206]:
- 10 or morePathogenic
- 6 to 9Likely pathogenic
- 0 to 5Uncertain significance
- −1 to −6Likely benign
- −7 or lessBenign
A simplified illustration, not a real classification. Imagine a new TRPV4 change in the ankyrin repeat domain. It is absent from population databases (+1), sits in a known hotspot (+2), and prediction tools call it damaging (+1). Total: 4 points, so it is a VUS. Then both parents are tested, neither carries it, and parentage is confirmed: de novo, strong evidence (+4). New total: 8, so it is likely pathogenic. Nothing about the variant changed. The evidence did.
How often, and how fast
| Study | Who was tested | What happened to VUS |
|---|---|---|
| Chen et al., 2023 [210] | 1.69 million people tested with multigene panels across many specialties, including neurology (one lab, 2014 to 2022) | 7.3% of distinct VUS were reclassified. 80% moved to benign or likely benign and about 20% moved up. On average it took about 31 months to downgrade and 22 months to upgrade. VUS were more common in non-White groups, who are under-represented in genetic databases. |
| Mersch et al., 2018 [209] | 1.45 million people tested for hereditary cancer genes (one lab) | 7.7% of distinct VUS were reclassified: 91% down and 9% up. Pathogenic results changed category only 0.7% of the time. |
| Krenn et al., 2024 [211] | 263 adults with neuromuscular disorders (exome or genome sequencing) | Re-review solved 7 of 23 uncertain cases (30%), using new clinical information, better prediction tools and family testing. It also moved 3 of 53 “solved” cases back to uncertain. |
| Østern et al., 2014 [212] | Norwegian families with CMT | Testing relatives reclassified several CMT variants, both up and down. |
No study has measured reclassification rates for TRPV4 or CMT specifically. Most of the large numbers come from cancer genes or mixed panels, so treat them as a general picture, not a prediction for any one variant.
Reclassification in TRPV4: real examples
- Lab testing changed 9 of 19 classifications. Researchers at Johns Hopkins and elsewhere tested 30 TRPV4 variants for channel overactivity and cell toxicity, then re-applied the ACMG rules. Adding their results “changed the ACMG classification for 9 of 19 clinical variants analysed”. Five VUS moved to likely benign, one likely pathogenic variant moved to likely benign, two moved from likely pathogenic to VUS, and one moved from pathogenic to likely pathogenic [22].
- A clinical pattern emerged. Overactive (gain-of-function) variants went with onset at birth, vocal cord weakness and motor-predominant disease. People whose variants behaved normally “often demonstrated late-onset and sensory-predominant disease” [22].
- Public databases lag behind research. p.Ser93Phe (S93F) is listed in GeneReviews and was found to be overactive in 2025, but ClinVar still lists it as a VUS [217]. If your variant is uncertain, a recent paper may know more than the database.
- Lab results can disagree. p.Pro97Arg (P97R) was reported as less active in 2012 and as clearly overactive in 2025 [22]. One of the 2010 discovery papers also reported reduced activity for variants that later work showed to be overactive, a debate covered on the biology page. This is one reason a single experiment counts only as supporting evidence.
How a new classification reaches you
Not automatically. ACMG says re-review “may be initiated upon external request (by the clinical team or patient), or by the laboratory”, and that labs may charge for it [214]. Responsibility for recontacting patients is shared between the lab, your doctors and you, and “no definitive answers currently exist” [215]. ClinGen's patient registry notes that updated information “is not always shared with the patient by testing laboratories” [226]. In practice, you often have to ask.
The trend is encouraging. Two leading genetics researchers argued in 2024 that “many, if not most, VUS in coding regions will be resolved by 2030”, thanks to large-scale lab testing, better prediction tools and data sharing [213].
Possible steps if you have a VUS
These are ideas, not instructions. They come from genetics guidance and research on uncertain results, and none of them is required. Your genetic counselor or doctor can help you decide which, if any, make sense for you.
- Talking with a genetic counselor is a good first step if you have not had the chance yet. In the US and Canada, the “Find a Genetic Counselor” directory of the National Society of Genetic Counselors (NSGC) lists over 3,300 counselors, with telehealth options [232]. The CMT Genie program offers telehealth genetic counseling for people with signs of CMT [88].
- Asking for a re-review every year or two, or when something changes (a new symptom, a new test result or a newly tested relative), is one option. ACMG encourages labs to ask for updated clinical and family history, so it can help to have yours ready [214].
- Testing relatives can add evidence. Testing both parents can show whether the variant is new (de novo). Testing affected and unaffected relatives can show whether it follows the condition. A genetic counselor can say which relatives would be most informative [207].
- Checking ClinVar yourself is another option. Searching for the gene and protein change shows the overall classification, the star rating and each lab's submission [217]:
- 4 stars: practice guideline. 3 stars: expert panel. 2 stars: several labs agree. 1 star: one lab, or labs disagree. No stars: no criteria given.
- “Conflicting classifications” means labs disagree across levels, for example one says pathogenic and another uncertain.
- No TRPV4 variant currently has 3 or 4 stars.
- Joining a registry or natural history study is another possibility. Clinical details from people with uncertain results are exactly the evidence that resolves VUS. Options include the Inherited Neuropathy Consortium natural history study [52], GRIN (the Global Registry for Inherited Neuropathies) [55], and GenomeConnect, ClinGen's patient registry, which shares data with ClinVar and can send you updates [226].
- Asking whether re-analysis makes sense may be worthwhile if you had exome or genome sequencing. Across 29 studies, re-analyzing existing data found a new diagnosis in about 10% of cases, mostly because of newly published research [228].
- Keeping your contact details up to date with the lab that ran the test and the clinic that ordered it means they can reach you if anything changes.
Well-documented TRPV4 neuromuscular variants
GeneReviews names seven variants as “the most commonly reported and best validated pathogenic TRPV4 variants” [6]. All seven change an arginine (Arg, R) on the same exposed surface of the ankyrin repeat domain, the part of the protein inside the cell that RhoA binds to [6]. In the registry of 68 people, variants in this domain made up 94% of neuropathy-causing variants, and R269H was the most common [3].
How to read the tables: “Features and reports” summarizes the papers behind this page, not a worldwide count of families. ClinVar status was checked on 11 October 2026; stars (out of 4) show how well reviewed a classification is. All DNA positions use NM_021625.5.
| Variant | ClinVar | Conditions reported | Features and reports | Lab evidence |
|---|---|---|---|---|
| p.Arg186GlnR186Q · c.557G>A · my variant | Pathogenic / likely pathogenic ★★ ClinVar 39419 | CMT2C; congenital spinal muscular atrophy with joint contractures (arthrogryposis) | First described in one family in 2012: distal weakness, hoarse voice, noisy breathing on exertion, and involvement of the vocal folds and the nerve to the diaphragm; 2 of 3 affected members had scoliosis [218]. Also reported in a person with onset before age 5 and skeletal features, and in a family where not every carrier was affected [28]. | Overactive channel and increased cell death, blocked by a channel blocker [218]; confirmed as gain of function in 2025 [22]. |
| p.Arg232CysR232C · c.694C>T | Pathogenic ★★ ClinVar 30472 | CMT2C; distal motor neuropathy with vocal fold weakness; SPSMA; congenital distal SMA; overlap with skeletal features | First reported in three UK and Swiss families [17], with more families and individuals since [219]. In one family, some members had vocal cord and diaphragm involvement and others did not [219]. | Overactive channel; disrupts RhoA binding [24]. Mice carrying it develop weakness and motor neuron loss, rescued by a TRPV4 blocker [15]. |
| p.Arg269HisR269H · c.806G>A | Pathogenic / likely pathogenic ★★ ClinVar 5000 | CMT2C; congenital distal SMA with arthrogryposis; SPSMA; mixed with skeletal dysplasia | One of the original 2010 variants, found in several families [10]. The most common variant in the registry, with the earliest age of onset; age and severity were only weakly linked [3]. Among the variants most often seen with both nerve and bone features [6]. | Overactive channel, toxic to nerve cells [10]; confirmed in 2025 [22]. |
| p.Arg269CysR269C · c.805C>T | Pathogenic ★★ ClinVar 5002 | CMT2C; motor neuropathy; SPSMA; congenital SMA with arthrogryposis | One of the original 2010 variants [10]. In one Spanish family, a mother had moderate weakness, her daughter had severe congenital SMA with vocal cord paresis, and three carriers aged 9, 40 and 70 had normal examinations [222]. Also seen as a new (de novo) change [230]. | Overactive channel [10]; disrupts RhoA binding [24]; fruit fly [26] and mouse [15] models. |
| p.Arg315TrpR315W · c.943C>T | Pathogenic / likely pathogenic ★★ ClinVar 4999 | CMT2C; SPSMA; congenital distal SMA; one de novo case with skeletal dysplasia | One of the original 2010 variants. One large family had ten living affected members, ranging from mild to severe, with different diagnoses within the family [12]. Age and severity were only weakly linked in the registry [3]. Vocal cord paresis ranged from absent to severe in reported families [220]. | Disrupts RhoA binding [24]; gain of function in the 2025 study [22]. |
| p.Arg316CysR316C · c.946C>T | Pathogenic ★★ ClinVar 5001 | SPSMA; CMT2C; overlap | Found in a large family with scapuloperoneal SMA, where it followed the condition [14], and in CMT2C families [12]. In a family reported in 2023, the father had weakness, while his son was born with clubfoot but had no obvious weakness [224]. | Gain of function in the 2025 study [22]. |
| p.Arg316HisR316H · c.947G>A | Pathogenic / likely pathogenic ★★ ClinVar 30473 | CMT2C | First reported as a new (de novo) change in a person with CMT2C [219]. | Overactive channel and cell death, reversible with a channel blocker [219]; confirmed in 2025 [22]. |
Other documented neuromuscular variants
| Variant | ClinVar | Conditions reported | Features and reports | Lab evidence |
|---|---|---|---|---|
| p.Arg237LeuR237L · c.710G>T | Likely pathogenic ★ ClinVar 536862 | CMT2C | One family. One person had weakness of both vocal folds, which moved at 15 to 20% of normal [221]. | Overactive and toxic [221]; RhoA could not restrain it [24]. |
| p.Arg237GlyR237G · c.709C>G | Pathogenic ★ ClinVar 1073853 | CMT2C | One family [221]. | Overactive, with marked toxicity [221]. |
| p.Ser542TyrS542Y · c.1625C>A | Pathogenic ★ ClinVar 30469 | CMT2C with vocal cord paresis and short stature | A family spanning several generations, with mild neuropathy and pronounced short stature [220]. One of the most common variants with both nerve and bone features [6]. | Strongly overactive [28]. |
| p.Val620IleV620I · c.1858G>A | Pathogenic / likely pathogenic ★★ ClinVar 4993 | Axonal neuropathy with brachyolmia-like skeletal features | First known as a skeletal (brachyolmia) variant; later found as a new change in a person with neuropathy [17]. | Activating [12]. |
| p.Pro97ArgP97R · c.290C>G | Pathogenic ★ ClinVar 234619 | Congenital distal SMA with vocal cord paralysis | One child. It lies outside the ankyrin repeat domain, in a flexible region near the start of the protein [22]. | Conflicting: reported as less active in 2012 and overactive in 2025 [22]. |
More variants on Stephanie Carmody's list
In 2024 Stephanie Carmody, who started the TRPV4 patient group on Facebook, put together a chart of TRPV4 variants with Dr. Brett McCray, based on his team's research. As well as the variants in the tables above, it counts the ones below as pathogenic or likely pathogenic. Their formal classifications do not all match the chart yet, so each row says what ClinVar and the 2025 lab study from Dr. McCray's team show. ClinVar was checked on 14 October 2026.
| Variant | ClinVar | What is known |
|---|---|---|
| p.Arg232ProR232P · c.695G>C | Likely pathogenic ★ ClinVar 1493962 | Another change at the R232 hotspot, classified by one lab for CMT2C [217]. |
| p.Arg237GlnR237Q · c.710G>A | Conflicting ★ ClinVar 1679171 | The same position as R237L and R237G above. Labs are split between likely pathogenic and uncertain [217]. |
| p.Arg616GlyR616G | Not in ClinVar | Strongly overactive in the 2025 lab study, which calls it a known pathogenic change and lists it with severe neuropathy and no skeletal dysplasia [22]. |
| p.Leu619ProL619P | Not in ClinVar | Strongly overactive in the 2025 lab study, which lists it as a known pathogenic change [22]. |
| p.Trp785CysW785C · c.2355G>C | Likely pathogenic ★ ClinVar 4292777 | Strongly overactive in the 2025 lab study, which lists it as a known pathogenic change [22]. One submitting lab in ClinVar [217]. |
| p.Ser93PheS93F | Uncertain significance ★ ClinVar 2636347 | Overactive in the 2025 lab study, but still formally a VUS there and in ClinVar [22]. See variants still uncertain. |
| p.Ser94LeuS94L · c.281C>T | Conflicting ★ ClinVar 216734 | Moderately overactive in the 2025 lab study, but so far linked to neuropathy only when a person has inherited it from both parents (homozygous). It is still formally a VUS there, and labs disagree in ClinVar [22]. |
The same chart also lists variants it considers benign or uncertain. Its benign labels come mainly from lab tests that showed no overactivity, and several of those variants are still formally uncertain, or even likely pathogenic, in ClinVar or in the 2025 study [22]. So they are not repeated here. If your variant is on that list, a genetic counselor can help you read it.
Same variant, different lives
One of the most consistent findings in TRPV4 disease is that a variant does not predict a person's course. The registry found “marked heterogeneity in symptoms, severity and age of onset, even among family members with the same TRPV4 mutation”, and the same variant can cause a CMT or an SMA picture within one family [3]. GeneReviews notes that symptoms can be so mild they go unrecognized, and that limb weakness and voice or breathing problems do not track each other [6]. One 2010 study alone identified six carriers without symptoms [17]. Even different changes at the same position can have different effects: at position 616, one change caused severe neuropathy while another caused only skeletal dysplasia [28].
So the tables above describe what has been reported, not what any one person will experience.
Examples of variants still uncertain
| Variant | ClinVar | Why it is uncertain |
|---|---|---|
| p.Ser93PheS93F | Uncertain significance ★ ClinVar 2636347 | Listed in GeneReviews and shown to be overactive in 2025, but not yet reclassified in ClinVar [6]. A likely candidate for an upgrade. |
| p.Arg232SerR232S | Uncertain significance no stars ClinVar 637419 | A different change at the R232 hotspot. One submission, and no published lab study found. |
| p.Thr701IleT701I | Uncertain significance no stars ClinVar 637421 | Called “potentially pathogenic” in 2012 based on computer predictions only; no lab testing found. |
| p.Arg232HisR232H | Conflicting ★ ClinVar 246538 | Labs disagree: two call it uncertain and one likely pathogenic. |
About half of all TRPV4 entries in ClinVar are VUS (about 665 of 1,360), and almost all of them come from a single submitting lab [217]. Many are probably harmless. Some will turn out to matter. The evidence described above tells them apart, and much of it comes from patients and families taking part in research.
ClinVar figures and classifications on this page were checked on 11 October 2026 (14 October for the variants on Stephanie Carmody’s list) and will change over time. Follow the ClinVar links for the current status.