chr12-109793560-G-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Moderate
The NM_021625.5(TRPV4):c.1625C>A(p.Ser542Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S542C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_021625.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRPV4 | NM_021625.5 | c.1625C>A | p.Ser542Tyr | missense_variant | 10/16 | ENST00000261740.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPV4 | ENST00000261740.7 | c.1625C>A | p.Ser542Tyr | missense_variant | 10/16 | 1 | NM_021625.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease axonal type 2C Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 05, 2022 | This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 542 of the TRPV4 protein (p.Ser542Tyr). For these reasons, this variant has been classified as Pathogenic. 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: 30469). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease and short stature (PMID: 21115951). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 30, 2010 | - - |
Neuromuscular disease;C0410528:Skeletal dysplasia Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at