rs1060500151

Variant names:

• chr1-237808934-G-A
• rs1060500151
• NM_001035.3:c.14332G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-237808934-G-A
• chr1-237808934-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_001035.3(RYR2):​c.14332G>A​(p.Val4778Ile) 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. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V4778L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.96

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 Likely_pathogenic. Variant got 6 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, 5 uncertain in NM_001035.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the RYR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. Gene score misZ: 5.7809 (above the threshold of 3.09). Trascript score misZ: 6.4158 (above the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.14332G>A	p.Val4778Ile	missense_variant	Exon 100 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.14332G>A	p.Val4778Ile	missense_variant	Exon 100 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.*5424G>A		non_coding_transcript_exon_variant	Exon 99 of 104	5		ENSP00000499659.2
RYR2	ENST00000609119.2	n.*5424G>A		3_prime_UTR_variant	Exon 99 of 104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Mar 28, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in individual(s) with cardiomyopathy and/or arrhythmia in published literature (PMID: 26688388); Not observed at significant frequency in large population cohorts (gnomAD); Located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26688388, 19926015) -

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Nov 27, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces valine with isoleucine at codon 4778 of the RYR2 protein (p.Val4778Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant has been observed in individual(s) affected with sudden cardiac death (PMID: 26688388). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.83	N;.
REVEL	Uncertain	0.61
Sift	Benign	0.19	T;.
Polyphen		0.99	D;.
Vest4		0.80
MutPred		0.64		Loss of sheet (P = 0.1158);.;
MVP		0.91
MPC		1.5
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.26
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060500151; hg19: chr1-237972234;