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

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 4, 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:: RCV000197485.13

Allele description

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 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000255062	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 4, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000375878	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 12, 2018)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000255062

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 4, 2024)

germline

clinical testing

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

SCV000375878

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 12, 2018)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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, SCV000255062.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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 (Invitae). ClinVar contains an entry for this variant (Variation ID: 216733). 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 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000375878.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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