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NM_021625.5(TRPV4):c.695G>A (p.Arg232His) AND Charcot-Marie-Tooth disease axonal type 2C

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Apr 4, 2024
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002519834.3

Allele description [Variation Report for NM_021625.5(TRPV4):c.695G>A (p.Arg232His)]

NM_021625.5(TRPV4):c.695G>A (p.Arg232His)

Gene:
TRPV4:transient receptor potential cation channel subfamily V member 4 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12q24.11
Genomic location:
Preferred name:
NM_021625.5(TRPV4):c.695G>A (p.Arg232His)
HGVS:
  • NC_000012.12:g.109803008C>T
  • NG_017090.1:g.35400G>A
  • NM_001177428.1:c.695G>A
  • NM_001177431.1:c.593G>A
  • NM_001177433.1:c.695G>A
  • NM_021625.5:c.695G>AMANE SELECT
  • NM_147204.2:c.695G>A
  • NP_001170899.1:p.Arg232His
  • NP_001170902.1:p.Arg198His
  • NP_001170904.1:p.Arg232His
  • NP_067638.3:p.Arg232His
  • NP_067638.3:p.Arg232His
  • NP_671737.1:p.Arg232His
  • LRG_372t1:c.695G>A
  • LRG_372:g.35400G>A
  • LRG_372p1:p.Arg232His
  • NC_000012.11:g.110240813C>T
  • NM_021625.4:c.695G>A
Protein change:
R198H
Links:
dbSNP: rs769107613
NCBI 1000 Genomes Browser:
rs769107613
Molecular consequence:
  • NM_001177428.1:c.695G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001177431.1:c.593G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001177433.1:c.695G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_021625.5:c.695G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_147204.2:c.695G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Charcot-Marie-Tooth disease axonal type 2C (HMSN2C)
Synonyms:
Charcot-Marie-Tooth disease type 2C; Hereditary motor and sensory neuropathy 2 C; CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2C; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0011633; MedGen: C1853710; OMIM: 606071

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV003501342Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Dec 18, 2021)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004809484Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Apr 4, 2024)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

TRPV4 mutations in children with congenital distal spinal muscular atrophy.

Fiorillo C, Moro F, Brisca G, Astrea G, Nesti C, Bálint Z, Olschewski A, Meschini MC, Guelly C, Auer-Grumbach M, Battini R, Pedemonte M, Romano A, Menchise V, Biancheri R, Santorelli FM, Bruno C.

Neurogenetics. 2012 Aug;13(3):195-203. doi: 10.1007/s10048-012-0328-7. Epub 2012 Apr 25.

PubMed [citation]
PMID:
22526352

Structural and biochemical consequences of disease-causing mutations in the ankyrin repeat domain of the human TRPV4 channel.

Inada H, Procko E, Sotomayor M, Gaudet R.

Biochemistry. 2012 Aug 7;51(31):6195-206. Epub 2012 Jul 25.

PubMed [citation]
PMID:
22702953
PMCID:
PMC3413242
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV003501342.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg232 amino acid residue in TRPV4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22526352, 22702953, 24789864, 26048687). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt TRPV4 protein function. ClinVar contains an entry for this variant (Variation ID: 246538). This variant has not been reported in the literature in individuals affected with TRPV4-related conditions. This variant is present in population databases (rs769107613, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 232 of the TRPV4 protein (p.Arg232His).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004809484.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 15, 2024