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NM_021625.5(TRPV4):c.2389G>A (p.Glu797Lys) AND Charcot-Marie-Tooth disease axonal type 2C

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Aug 10, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001851964.13

Allele description

NM_021625.5(TRPV4):c.2389G>A (p.Glu797Lys)

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.2389G>A (p.Glu797Lys)
Other names:
E797K
HGVS:
  • NC_000012.12:g.109784385C>T
  • NG_017090.1:g.54023G>A
  • NM_001177428.1:c.2248G>A
  • NM_001177431.1:c.2287G>A
  • NM_001177433.1:c.2068G>A
  • NM_021625.5:c.2389G>AMANE SELECT
  • NM_147204.2:c.2209G>A
  • NP_001170899.1:p.Glu750Lys
  • NP_001170902.1:p.Glu763Lys
  • NP_001170904.1:p.Glu690Lys
  • NP_067638.3:p.Glu797Lys
  • NP_067638.3:p.Glu797Lys
  • NP_671737.1:p.Glu737Lys
  • LRG_372t1:c.2389G>A
  • LRG_372:g.54023G>A
  • LRG_372p1:p.Glu797Lys
  • NC_000012.11:g.110222190C>T
  • NM_021625.4:c.2389G>A
  • NM_021625.4:c.[2389G>A]
  • Q9HBA0:p.Glu797Lys
Protein change:
E690K; GLU797LYS
Links:
UniProtKB: Q9HBA0#VAR_064537; OMIM: 605427.0018; dbSNP: rs267607149
NCBI 1000 Genomes Browser:
rs267607149
Molecular consequence:
  • NM_001177428.1:c.2248G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001177431.1:c.2287G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001177433.1:c.2068G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_021625.5:c.2389G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_147204.2:c.2209G>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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002242998Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Aug 10, 2023) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Molecular diagnosis in a cohort of 114 patients with rare skeletal dysplasias.

Silveira KC, Kanazawa TY, Silveira C, Lacarrubba-Flores MDJ, Carvalho BS, Cavalcanti DP.

Am J Med Genet C Semin Med Genet. 2021 Sep;187(3):396-408. doi: 10.1002/ajmg.c.31937. Epub 2021 Sep 16.

PubMed [citation]
PMID:
34529350

Increased basal activity is a key determinant in the severity of human skeletal dysplasia caused by TRPV4 mutations.

Loukin S, Su Z, Kung C.

PLoS One. 2011 May 5;6(5):e19533. doi: 10.1371/journal.pone.0019533.

PubMed [citation]
PMID:
21573172
PMCID:
PMC3088684
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV002242998.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

ClinVar contains an entry for this variant (Variation ID: 18435). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu797 amino acid residue in TRPV4. Other variant(s) that disrupt this residue have been observed in individuals with TRPV4-related conditions (PMID: 34529350), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 21573172, 26170305). 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. This missense change has been observed in individuals with clinical features of spondylometaphyseal dysplasia (PMID: 20425821, 20503319, 20577006; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 797 of the TRPV4 protein (p.Glu797Lys).

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

Last Updated: Sep 16, 2024