1-237783851-G-C

Position:

• chr1-237783851-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001035.3(RYR2):​c.12139G>C​(p.Asp4047His) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• 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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.12139G>C	p.Asp4047His	missense_variant	90/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.12139G>C	p.Asp4047His	missense_variant	90/105	1	NM_001035.3	ENSP00000355533	P1
RYR2	ENST00000660292.2	c.12160G>C	p.Asp4054His	missense_variant	91/106			ENSP00000499787
RYR2	ENST00000659194.3	c.12127G>C	p.Asp4043His	missense_variant	90/105			ENSP00000499653
RYR2	ENST00000609119.2	c.*3231G>C		3_prime_UTR_variant, NMD_transcript_variant	89/104	5		ENSP00000499659

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 19, 2017

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp4047Hi s variant in RYR2 has been identified by our laboratory in one Caucasian individ ual with CPVT and segregated with disease in one relative with CPVT, one relativ e with PSVT, and in one relative with suspected CPVT. It was absent from large p opulation studies. Computational prediction tools and conservation analysis sugg est that the p.Asp4047His variant may impact the protein, though this informatio n is not predictive enough to determine pathogenicity. In summary, while there i s some suspicion for a pathogenic role, the clinical significance of the p.Arg40 47His variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 29, 2019

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance and reported to segregate with suspected or confirmed CPVT or PSVT in three affected relatives (ClinVar Variant ID# 179754; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect -

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 18, 2020

This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 179754). This sequence change replaces aspartic acid with histidine at codon 4047 of the RYR2 protein (p.Asp4047His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.64
MutPred		0.30		Gain of methylation at K4045 (P = 0.0568);.;
MVP		0.93
MPC		2.1
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.77
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: rs727505103; hg19: chr1-237947151;