12-109800666-G-T

Position:

• chr12-109800666-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP5_Moderate

The NM_021625.5(TRPV4):​c.805C>A​(p.Arg269Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R269C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.03

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_021625.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-109800666-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, TRPV4
• PP5: Variant 12-109800666-G-T is Pathogenic according to our data. Variant chr12-109800666-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 536867.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPV4	NM_021625.5	c.805C>A	p.Arg269Ser	missense_variant	5/16	ENST00000261740.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPV4	ENST00000261740.7	c.805C>A	p.Arg269Ser	missense_variant	5/16	1	NM_021625.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 29, 2022

This variant disrupts the p.Arg269 amino acid residue in TRPV4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20037586, 20037587, 20037588, 24789864, 25900305, 26110311). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 536867). This missense change has been observed in individual(s) with TRPV4-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 269 of the TRPV4 protein (p.Arg269Ser). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T;.;.
Eigen	Benign	-0.0096
Eigen_PC	Benign	0.080
FATHMM_MKL	Benign	0.68	D
M_CAP	Uncertain	0.096	D
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Uncertain	0.092	D
MutationAssessor	Benign	0.010	N;N;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.59	N;N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.61	T;T;T;T
Sift4G	Benign	0.73	T;T;T;T
Polyphen		0.99	D;D;D;B
Vest4		0.78
MutPred		0.60		Gain of catalytic residue at F273 (P = 0.0121);Gain of catalytic residue at F273 (P = 0.0121);Gain of catalytic residue at F273 (P = 0.0121);.;
MVP		0.94
MPC		0.94
ClinPred		0.92	D
GERP RS		4.9
Varity_R		0.83
gMVP		0.80

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: rs267607146; hg19: chr12-110238471; COSMIC: COSV99924961;