ClinVar Genomic variation as it relates to human health
NM_021625.5(TRPV4):c.947G>A (p.Arg316His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_021625.5(TRPV4):c.947G>A (p.Arg316His)
Variation ID: 30473 Accession: VCV000030473.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.11 12: 109798819 (GRCh38) [ NCBI UCSC ] 12: 110236624 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 21, 2015 May 12, 2024 Oct 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_021625.5:c.947G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_067638.3:p.Arg316His missense NM_001177428.1:c.806G>A NP_001170899.1:p.Arg269His missense NM_001177431.1:c.845G>A NP_001170902.1:p.Arg282His missense NM_001177433.1:c.806G>A NP_001170904.1:p.Arg269His missense NM_147204.2:c.947G>A NP_671737.1:p.Arg316His missense NC_000012.12:g.109798819C>T NC_000012.11:g.110236624C>T NG_017090.1:g.39589G>A LRG_372:g.39589G>A LRG_372t1:c.947G>A LRG_372p1:p.Arg316His Q9HBA0:p.Arg316His - Protein change
- R316H, R269H, R282H
- Other names
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- Canonical SPDI
- NC_000012.12:109798818:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TRPV4 | - | - |
GRCh38 GRCh37 |
1129 | 1144 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 22, 2023 | RCV000023430.20 | |
not provided (1) |
no classification provided
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- | RCV000202476.10 | |
Pathogenic (1) |
no assertion criteria provided
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Mar 18, 2016 | RCV000415397.10 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2023 | RCV000497541.17 | |
Uncertain significance (1) |
no assertion criteria provided
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Aug 14, 2019 | RCV000856932.9 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jan 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease axonal type 2C
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368140.2
First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic.
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Pathogenic
(Feb 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease axonal type 2C
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175628.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The TRPV4 c.947G>A variant is classified as a PATHOGENIC variant (PS4, PS3, PM1, PP3) The variant is a single nucleotide change in exon 6/16 of … (more)
The TRPV4 c.947G>A variant is classified as a PATHOGENIC variant (PS4, PS3, PM1, PP3) The variant is a single nucleotide change in exon 6/16 of the TRPV4 gene, which is predicted to change the amino acid arginine at position 316 in the protein to histidine. The variant has been previously identified in multiple unrelated individuals with CMT or neuropathies (PMID: 2128891, 24319099, 24789864, ClinVar 2023) (PS4). In vitro functional studies have shown that the variant affects TRPV4 function, causing increased intracellular calcium and decreased cell viability (PMID: 21288981) (PS3). Other pathogenic/ likely pathogenic variants at the same amino acid residue (or nearby) have been previously reported. This suggests that this residue (p.Arg316) is clinically significant, and the variant is located in an active site of the gene (PM1). The variant is in dbSNP (rs387906905) but is absent from population databases. The variant has been reported in ClinVar (Variation ID: #30473) and HGMD (Accession no.: CM111783) as pathogenic/ likely pathogenic/ disease causing. Computational predictions support a deleterious effect on the gene or gene product (PP3.) (less)
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Likely pathogenic
(Apr 05, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV000590825.1
First in ClinVar: Aug 20, 2017 Last updated: Aug 20, 2017 |
Observation 1:
Clinical Features:
leg weakness (present) , abnormal reflex (present) , abnormal gait (present) , distal congenital non-progressive spinal muscular atrophy (present)
Age: 0-9 years
Sex: female
Observation 2:
Clinical Features:
hypotonia (present) , abnormal gait (present)
Age: 0-9 years
Sex: female
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Pathogenic
(Oct 15, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001795764.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Observed in an individual with distal hereditary motor neuropathy and vocal paresis and was found to segregate with disease in a family with arthrogryposis multiplex … (more)
Observed in an individual with distal hereditary motor neuropathy and vocal paresis and was found to segregate with disease in a family with arthrogryposis multiplex congenita (Echaniz-Laguna et al., 2014; Laquerriere et al., 2014); Functional studies suggest that R316H results in a gain of function of TRPV4, causing increased intracellular calcium and decreased cell viability (Klein et al., 2011).; In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31701603, 24830047, 25256292, 24319099, 24789864, 21288981) (less)
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Pathogenic
(Oct 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease axonal type 2C
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000767281.4
First in ClinVar: Mar 08, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 316 of the TRPV4 protein (p.Arg316His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 316 of the TRPV4 protein (p.Arg316His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease type 2C (CMT2C), scapuloperoneal spinal muscular atrophy (SPSMA), distal hereditary motor neuropathy (dHMN), and arthrogryposis multiplex congenita (AMC) (PMID: 21288981, 24319099, 24789864). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30473). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TRPV4 protein function. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 21288981). This variant disrupts the p.Arg316 amino acid residue in TRPV4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20037587, 20037588, 21454511, 24789864). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004131872.5
First in ClinVar: Nov 20, 2023 Last updated: May 12, 2024 |
Comment:
TRPV4: PM2, PM5, PS2:Moderate, PS4:Moderate, PP1, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Mar 18, 2016)
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no assertion criteria provided
Method: clinical testing
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EMG abnormality
Lower limb amyotrophy Clubfoot
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492580.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
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Uncertain significance
(Aug 14, 2019)
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no assertion criteria provided
Method: research
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Genesis Genome Database
Accession: SCV000999496.1
First in ClinVar: Dec 06, 2019 Last updated: Dec 06, 2019 |
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Pathogenic
(Mar 08, 2011)
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no assertion criteria provided
Method: literature only
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HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000044721.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2023 |
Comment on evidence:
In a 30-year-old man with HMSN2C (606071), Klein et al. (2011) identified a de novo heterozygous c.947G-A transition in exon 6 of the TRPV4 gene, … (more)
In a 30-year-old man with HMSN2C (606071), Klein et al. (2011) identified a de novo heterozygous c.947G-A transition in exon 6 of the TRPV4 gene, resulting in an arg316-to-his (R316H) substitution in a conserved residue in the ankyrin-repeat domain. In vitro functional expression studies showed that the mutant protein had the same subcellular localization as wildtype in HEK293 cells and localized to the plasma membrane similar to wildtype in HeLa cells. In HEK293 cells, the mutant protein caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. The mutation was not found in 800 controls. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Neuromuscular disease
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000148066.2
First in ClinVar: Dec 21, 2015 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Autosomal Dominant TRPV4 Disorders. | Adam MP | - | 2020 | PMID: 24830047 |
Phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathy. | Echaniz-Laguna A | Neurology | 2014 | PMID: 24789864 |
Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects. | Laquérriere A | Human molecular genetics | 2014 | PMID: 24319099 |
Mutant TRPV4-mediated toxicity is linked to increased constitutive function in axonal neuropathies. | Fecto F | The Journal of biological chemistry | 2011 | PMID: 21454511 |
TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies. | Klein CJ | Neurology | 2011 | PMID: 21288981 |
Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. | Auer-Grumbach M | Nature genetics | 2010 | PMID: 20037588 |
Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. | Deng HX | Nature genetics | 2010 | PMID: 20037587 |
The mucopolysaccharidoses. Diagnosis, molecular genetics and treatment. | Hopwood JJ | Molecular biology & medicine | 1990 | PMID: 2128891 |
Text-mined citations for rs387906905 ...
HelpRecord last updated Jun 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.