12-109798820-G-T

Variant names:

• chr12-109798820-G-T
• rs267607145
• NM_021625.5:c.946C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP5_Moderate

The NM_021625.5(TRPV4):​c.946C>A​(p.Arg316Ser) 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. R316H) has been classified as Likely 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: 3.03
• Publications: 28 publications found

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]

TRPV4 Gene-Disease associations (from GenCC):

• metatropic dysplasia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• neuromuscular disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• spondylometaphyseal dysplasia, Kozlowski type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• TRPV4-related bone disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• autosomal dominant brachyolmia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• Charcot-Marie-Tooth disease axonal type 2C

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• scapuloperoneal spinal muscular atrophy, autosomal dominant

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• familial avascular necrosis of femoral head

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial digital arthropathy-brachydactyly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neuronopathy, distal hereditary motor, autosomal dominant 8

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• parastremmatic dwarfism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 4 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 chr12-109798819-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 12-109798820-G-T is Pathogenic according to our data. Variant chr12-109798820-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 424307.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPV4	NM_021625.5	c.946C>A	p.Arg316Ser	missense_variant	Exon 6 of 16	ENST00000261740.7	NP_067638.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPV4	ENST00000261740.7	c.946C>A	p.Arg316Ser	missense_variant	Exon 6 of 16	1	NM_021625.5	ENSP00000261740.2

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

not provided Pathogenic:1

Mar 20, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant that is likely pathogenic has been identified in the TRPV4 gene. The R316S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R316S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R316S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Additionally, different missense variants at the same position (R316C and R316H) and a nearby residue (R315W) have been reported in Human Gene Mutation Database in association with TRPV-related disorders (Deng et al., 2010; Klein et al., 2011), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.27	T;T;.;.;.;.
Eigen	Benign	0.010
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	.;T;T;T;T;T
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.42	N;N;.;N;.;.
PhyloP100		3.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.48	N;N;N;N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.62	T;T;T;T;T;T
Sift4G	Benign	0.61	T;T;T;T;T;T
Polyphen		0.99	D;D;D;D;B;P
Vest4		0.76
MutPred		0.57		Gain of ubiquitination at K311 (P = 0.0338);Gain of ubiquitination at K311 (P = 0.0338);.;Gain of ubiquitination at K311 (P = 0.0338);.;.;
MVP		0.77
MPC		1.1
ClinPred		0.74	D
GERP RS		3.5
Varity_R		0.38
gMVP		0.80
Mutation Taster		=14/86	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267607145; hg19: chr12-110236625;