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NM_021625.5(TRPV4):c.2605G>A (p.Ala869Thr) AND Charcot-Marie-Tooth disease axonal type 2C

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Dec 16, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000197485.15

Allele description [Variation Report for NM_021625.5(TRPV4):c.2605G>A (p.Ala869Thr)]

NM_021625.5(TRPV4):c.2605G>A (p.Ala869Thr)

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.2605G>A (p.Ala869Thr)
HGVS:
  • NC_000012.12:g.109783632C>T
  • NG_017090.1:g.54776G>A
  • NM_001177428.1:c.2464G>A
  • NM_001177431.1:c.2503G>A
  • NM_001177433.1:c.2284G>A
  • NM_021625.5:c.2605G>AMANE SELECT
  • NM_147204.2:c.2425G>A
  • NP_001170899.1:p.Ala822Thr
  • NP_001170902.1:p.Ala835Thr
  • NP_001170904.1:p.Ala762Thr
  • NP_067638.3:p.Ala869Thr
  • NP_067638.3:p.Ala869Thr
  • NP_671737.1:p.Ala809Thr
  • LRG_372t1:c.2605G>A
  • LRG_372:g.54776G>A
  • LRG_372p1:p.Ala869Thr
  • NC_000012.11:g.110221437C>T
  • NM_021625.4:c.2605G>A
Protein change:
A762T
Links:
dbSNP: rs138396764
NCBI 1000 Genomes Browser:
rs138396764
Molecular consequence:
  • NM_001177428.1:c.2464G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001177431.1:c.2503G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001177433.1:c.2284G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_021625.5:c.2605G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_147204.2:c.2425G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Charcot-Marie-Tooth disease axonal type 2C (HMSN2C)
Synonyms:
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2C; Charcot-Marie-Tooth Neuropathy Type 2C
Identifiers:
MONDO: MONDO:0011633; MedGen: C1853710; OMIM: 606071

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000255062Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Dec 16, 2024) 		germlineclinical testing

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

SCV000375878Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)		Uncertain significance
(Jan 12, 2018) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000255062.11

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 869 of the TRPV4 protein (p.Ala869Thr). This variant is present in population databases (rs138396764, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of TRPV4-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 216733). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TRPV4 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From Illumina Laboratory Services, Illumina, SCV000375878.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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

Last Updated: May 16, 2025