U.S. flag

An official website of the United States government

NM_021625.5(TRPV4):c.1729G>A (p.Val577Met) AND Charcot-Marie-Tooth disease axonal type 2C

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Dec 18, 2023
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:
RCV000706756.12

Allele description [Variation Report for NM_021625.5(TRPV4):c.1729G>A (p.Val577Met)]

NM_021625.5(TRPV4):c.1729G>A (p.Val577Met)

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.1729G>A (p.Val577Met)
HGVS:
  • NC_000012.12:g.109792747C>T
  • NG_017090.1:g.45661G>A
  • NM_001177428.1:c.1588G>A
  • NM_001177431.1:c.1627G>A
  • NM_001177433.1:c.1408G>A
  • NM_021625.5:c.1729G>AMANE SELECT
  • NM_147204.2:c.1549G>A
  • NP_001170899.1:p.Val530Met
  • NP_001170902.1:p.Val543Met
  • NP_001170904.1:p.Val470Met
  • NP_067638.3:p.Val577Met
  • NP_067638.3:p.Val577Met
  • NP_671737.1:p.Val517Met
  • LRG_372t1:c.1729G>A
  • LRG_372:g.45661G>A
  • LRG_372p1:p.Val577Met
  • NC_000012.11:g.110230552C>T
  • NM_021625.4:c.1729G>A
Protein change:
V470M
Links:
dbSNP: rs140535889
NCBI 1000 Genomes Browser:
rs140535889
Molecular consequence:
  • NM_001177428.1:c.1588G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001177431.1:c.1627G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001177433.1:c.1408G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_021625.5:c.1729G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_147204.2:c.1549G>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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000835825Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Dec 18, 2023)
germlineclinical testing

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

SCV001269264Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)
Likely benign
(Jan 13, 2018)
germlineclinical testing

Citation Link

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 Invitae, SCV000835825.6

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

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 577 of the TRPV4 protein (p.Val577Met). This variant is present in population databases (rs140535889, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TRPV4-related conditions. ClinVar contains an entry for this variant (Variation ID: 582636). 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. 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, SCV001269264.1

#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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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

Last Updated: May 1, 2024