chr12-109792401-A-G

Variant names:

• chr12-109792401-A-G
• rs515726163
• NM_021625.5:c.1853T>C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_021625.5(TRPV4):​c.1853T>C​(p.Leu618Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 8.95

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.

• PM1: In a transmembrane_region Helical (size 27) in uniprot entity TRPV4_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_021625.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TRPV4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 63 curated pathogenic missense variants (we use a threshold of 10). The gene has 35 curated benign missense variants. Gene score misZ: 1.9225 (below the threshold of 3.09). Trascript score misZ: 3.5609 (above the threshold of 3.09). GenCC associations: The gene is linked to TRPV4-related bone disorder, metatropic dysplasia, Charcot-Marie-Tooth disease axonal type 2C, spondylometaphyseal dysplasia, Kozlowski type, familial avascular necrosis of femoral head, parastremmatic dwarfism, neuromuscular disease, autosomal dominant brachyolmia, familial digital arthropathy-brachydactyly, neuronopathy, distal hereditary motor, autosomal dominant 8, scapuloperoneal spinal muscular atrophy, autosomal dominant.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 12-109792401-A-G is Pathogenic according to our data. Variant chr12-109792401-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 126473.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.1853T>C	p.Leu618Pro	missense_variant	Exon 12 of 16	ENST00000261740.7	NP_067638.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPV4	ENST00000261740.7	c.1853T>C	p.Leu618Pro	missense_variant	Exon 12 of 16	1	NM_021625.5	ENSP00000261740.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Metatropic dysplasia Pathogenic:2

May 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Jun 21, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The L618P pathogenic variant in the TRPV4 gene has been reported previously in at least two individuals with metatropic dysplasia, one of whom had a lethal phenotype and the other of whom had a non-lethal phenotype but was found to have the L618P variant in the mosaic state (Camacho et al., 2010; Weinstein et al., 2016). Functional studies demonstrate that L618P is associated with TRPV4 channel over-activity (Loukin et al., 2011). The L618P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L618P 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. We interpret L618P as a pathogenic variant. -

Skeletal dysplasia Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	.;D;D;D;T;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M;.;.;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.0	D;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0070	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.93
MutPred		0.79		Gain of catalytic residue at L623 (P = 0.0023);Gain of catalytic residue at L623 (P = 0.0023);.;.;.;.;
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs515726163; hg19: chr12-110230206;