rs397514494

chr12-109808298-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2 PP2 PP5_Very_Strong BP4

The NM_021625.5(TRPV4):c.557G>A(p.Arg186Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRPV4 NM_021625.5 missense, splice_region
• Scores: Splicing: ADA: 0.001436
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 0.608

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TRPV4
• PP5: Variant 12-109808298-C-T is Pathogenic according to our data. Variant chr12-109808298-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109808298-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.38614634).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPV4	NM_021625.5	c.557G>A	p.Arg186Gln	missense_variant, splice_region_variant	3/16	ENST00000261740.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPV4	ENST00000261740.7	c.557G>A	p.Arg186Gln	missense_variant, splice_region_variant	3/16	1	NM_021625.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461766 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	May 27, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 186 of the TRPV4 protein (p.Arg186Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of TRPV4-related conditions (PMID: 22675077, 24789864, 33060286; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39419). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 22675077). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2023	Published functional studies demonstrate a damaging effect on TRPV4 activity (Landoure et al., 2012); Observed in an individual with distal arthrogryposis in published literature; however, no further clinical information was provided (Ravenscroft et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20037586, 33467654, 24789864, 24830047, 22675077, 27549087, 31041394, 35170874, 33060286) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 02, 2016	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2019

- -

Neuronopathy, distal hereditary motor, autosomal dominant 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 27, 2014

- -

Neuromuscular disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;.;.;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.39	T;T;T;T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.8	L;L;L;L;L;.
MutationTaster	Benign	0.99	D;D;D;D;D;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.48	N;N;N;N;N;N
REVEL	Uncertain	0.48
Sift	Benign	0.20	T;T;T;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T;T
Polyphen		0.93	P;P;P;P;P;P
Vest4		0.81
MutPred		0.29		Gain of catalytic residue at T190 (P = 0.0254);Gain of catalytic residue at T190 (P = 0.0254);Gain of catalytic residue at T190 (P = 0.0254);Gain of catalytic residue at T190 (P = 0.0254);Gain of catalytic residue at T190 (P = 0.0254);.;
MVP		0.92
MPC		0.51
ClinPred		0.71	D
GERP RS		3.7
Varity_R		0.26
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.014
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: rs397514494; hg19: chr12-110246103;