NM_145068.4:c.2017C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_145068.4(TRPV3):c.2017C>T(p.Leu673Phe) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TRPV3
NM_145068.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.20

Publications

11 publications found

Variant links:

Genes affected

TRPV3 (HGNC:18084): (transient receptor potential cation channel subfamily V member 3) This gene product belongs to a family of nonselective cation channels that function in a variety of processes, including temperature sensation and vasoregulation. The thermosensitive members of this family are expressed in subsets of sensory neurons that terminate in the skin, and are activated at distinct physiological temperatures. This channel is activated at temperatures between 22 and 40 degrees C. This gene lies in close proximity to another family member gene on chromosome 17, and the two encoded proteins are thought to associate with each other to form heteromeric channels. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

TRPV3 Gene-Disease associations (from GenCC):

mutilating palmoplantar keratoderma with periorificial keratotic plaques
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet
Olmsted syndrome 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
isolated focal non-epidermolytic palmoplantar keratoderma
Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

TRPV3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.819

PP5

Variant 17-3518644-G-A is Pathogenic according to our data. Variant chr17-3518644-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 192256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPV3	NM_145068.4 link	c.2017C>T	p.Leu673Phe	missense_variant	Exon 15 of 18	ENST00000576742.6	NP_659505.1	Q8NET8-1
TRPV3	NM_001258205.2 link	c.2017C>T	p.Leu673Phe	missense_variant	Exon 15 of 18		NP_001245134.1	B2KYM6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPV3	ENST00000576742.6 link	c.2017C>T	p.Leu673Phe	missense_variant	Exon 15 of 18	1	NM_145068.4	ENSP00000461518.2		Q8NET8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1442246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

714964

African (AFR)

AF:

0.00

AC:

AN:

33366

American (AMR)

AF:

0.00

AC:

AN:

40798

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25628

East Asian (EAS)

AF:

0.00

AC:

AN:

39334

South Asian (SAS)

AF:

0.00

AC:

AN:

83072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102152

Other (OTH)

AF:

0.00

AC:

AN:

59870

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Olmsted syndrome 1

Pathogenic:1

Mar 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Isolated focal non-epidermolytic palmoplantar keratoderma

Pathogenic:1

Mar 06, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. -

not provided

Pathogenic:1

May 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 673 of the TRPV3 protein (p.Leu673Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Olmsted syndrome (PMID: 24452206, 28587736, 32795529; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 192256). 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 disruptive. Experimental studies have shown that this missense change affects TRPV3 function (PMID: 32795529). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

.;.;D;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.82

D;D;D;D

MetaSVM

Uncertain

0.71

MutationAssessor

Uncertain

2.1

.;M;M;M

PhyloP100

3.2

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.6

.;D;.;.

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

.;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;D;D

Vest4

0.97

MutPred

0.23

.;Loss of stability (P = 0.2506);Loss of stability (P = 0.2506);Loss of stability (P = 0.2506);

MVP

0.78

MPC

0.70

ClinPred

0.99

GERP RS

4.7

Varity_R

0.87

gMVP

0.85

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over