rs515726154

Positions:

• chr12-109794405-TAGA-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_021625.5(TRPV4):​c.1412_1414del​(p.Phe471del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPV4 NM_021625.5 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 9.17

Genes affected

TRPV4 (HGNC:18083): (transient receptor potential cation channel subfamily V member 4) This gene encodes a member of the OSM9-like transient receptor potential channel (OTRPC) subfamily in the transient receptor potential (TRP) superfamily of ion channels. The encoded protein is a Ca2+-permeable, nonselective cation channel that is thought to be involved in the regulation of systemic osmotic pressure. Mutations in this gene are the cause of spondylometaphyseal and metatropic dysplasia and hereditary motor and sensory neuropathy type IIC. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_021625.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 12-109794405-TAGA-T is Pathogenic according to our data. Variant chr12-109794405-TAGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109794405-TAGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPV4	NM_021625.5	c.1412_1414del	p.Phe471del	inframe_deletion	8/16	ENST00000261740.7	NP_067638.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPV4	ENST00000261740.7	c.1412_1414del	p.Phe471del	inframe_deletion	8/16	1	NM_021625.5	ENSP00000261740	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TRPV4: PS2, PM2, PS4:Moderate, PM4:Supporting, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 12, 2018	The TRPV4 c.1412_1414delTCT; p.Phe471del variant (rs515726154, ClinVar variant ID 126464) has been detected in at least two cases of metatropic dysplasia, one of which was infantile lethal (Camacho 2010, Dai 2010). Functional studies in Xenopus oocytes demonstrated that the p.Phe471del variant, like other established pathogenic TRPV4 variants, results in a phenotype consistent with a constitutively open calcium channel compared to wild-type, and similar gain-of-function mutations have been associated with disease in other TRP channel proteins (Loukin 2011). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Based on the available information, the p.Phe471del variant is likely to be a pathogenic variant associated with metatropic dysplasia. -

Charcot-Marie-Tooth disease axonal type 2C Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 03, 2023

This variant has been observed in individuals with clinical features of metatropic dysplasia (PMID: 20425821, 20577006, 22791502). This variant is not present in population databases (gnomAD no frequency). This variant, c.1412_1414del, results in the deletion of 1 amino acid(s) of the TRPV4 protein (p.Phe471del), but otherwise preserves the integrity of the reading frame. ClinVar contains an entry for this variant (Variation ID: 126464). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects TRPV4 function (PMID: 21573172). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. -

Skeletal dysplasia and progressive central nervous system degeneration, lethal Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Medicine Lab, University of California San Francisco

Mar 19, 2020

- -

Metatropic dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2010

- -

Skeletal dysplasia Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs515726154; hg19: chr12-110232210;