1-237798037-G-T

Position:

• chr1-237798037-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001035.3(RYR2):​c.13957G>T​(p.Val4653Phe) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V4653A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RYR2 NM_001035.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 10.0

Genes affected

RYR2 (HGNC:10484): (ryanodine receptor 2) This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-237798038-T-C is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR2. . Gene score misZ 5.7809 (greater than the threshold 3.09). Trascript score misZ 6.4158 (greater than threshold 3.09). GenCC has associacion of gene with hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 1-237798037-G-T is Pathogenic according to our data. Variant chr1-237798037-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 12961.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-237798037-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.13957G>T	p.Val4653Phe	missense_variant, splice_region_variant	97/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.13957G>T	p.Val4653Phe	missense_variant, splice_region_variant	97/105	1	NM_001035.3	ENSP00000355533	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Jul 05, 2022	ACMG Criteria: PS3, PS4, PM2_P, PP1, PP3, PP4; Variant was found in heterozygous state. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 29, 2004	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Nov 10, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.3	D;.
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.90
MutPred		0.73		Loss of MoRF binding (P = 0.0957);.;
MVP		0.96
MPC		2.0
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.84
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
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: rs121918604; hg19: chr1-237961337;