rs1060500142

chr1-237330939-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001035.3(RYR2):c.230C>T(p.Ala77Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A77A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.89

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 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001035.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RYR2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 1-237330939-C-T is Pathogenic according to our data. Variant chr1-237330939-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 404190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237330939-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.230C>T	p.Ala77Val	missense_variant	3/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.230C>T	p.Ala77Val	missense_variant	3/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.230C>T	p.Ala77Val	missense_variant	3/106
RYR2	ENST00000659194.3	c.230C>T	p.Ala77Val	missense_variant	3/105
RYR2	ENST00000609119.2	c.230C>T	p.Ala77Val	missense_variant, NMD_transcript_variant	3/104	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249222 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135198

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461686 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 02, 2023

Published in one family and segregated with both CPVT and ARVC in several relatives (d'Amati et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant may affect calcium release, which is thought to cause arrhythmia (Tang et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009); This variant is associated with the following publications: (PMID: 24025405, 19913485, 22221940, 16084945, 25901278, 31112425, 22374134) -

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 12, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RYR2 function (PMID: 19913485, 22374134). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 404190). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC), and catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 16084945; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 77 of the RYR2 protein (p.Ala77Val). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2019

The p.A77V variant (also known as c.230C>T), located in coding exon 3 of the RYR2 gene, results from a C to T substitution at nucleotide position 230. The alanine at codon 77 is replaced by valine, an amino acid with similar properties. This variant has been reported in a sudden death case with an arrhythmogenic right ventricular cardiomyopathy phenotype on autopsy and in two relatives with catecholaminergic polymorphic ventricular tachycardia (CPVT) as well as in an aborted cardiac arrest patient with CPVT (d'Amati G et al. Hum. Pathol., 2005 Jul;36:761-7; van der Werf C et al. Heart Rhythm, 2010 Oct;7:1383-9). Functional studies suggest this alteration impacts calcium signaling, but the physiological relevance of this impact is unclear (Tang Y. et al. Circ. Res., 2012 Mar;110(7):968-77). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lobo PA et al. Structure, 2009 Nov;17:1505-14; Tung CC et al. Nature, 2010 Nov;468:585-8; Walpoth BN et al. F1000Res, 2015 Jan;4:29). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.95		Gain of catalytic residue at A77 (P = 0.0983);.;
MVP		0.96
MPC		0.87
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.68
gMVP		0.59

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: rs1060500142; hg19: chr1-237494239; COSMIC: COSV63670229;