rs730880187

Variant names:

• chr1-237492973-C-T
• rs730880187
• NM_001035.3:c.1847C>T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001035.3(RYR2):​c.1847C>T​(p.Ser616Leu) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S616S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: 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 15 ACMG points.

• 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, 0.985
• PP5: Variant 1-237492973-C-T is Pathogenic according to our data. Variant chr1-237492973-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.1847C>T	p.Ser616Leu	missense_variant	Exon 19 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.1847C>T	p.Ser616Leu	missense_variant	Exon 19 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.1847C>T		non_coding_transcript_exon_variant	Exon 19 of 104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.1847C>T	p.Ser616Leu	missense_variant	Exon 19 of 106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.1847C>T	p.Ser616Leu	missense_variant	Exon 19 of 105			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:2

Jan 11, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been observed in individual(s) with clinical features of RYR2-related conditions (PMID: 19216760, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 180486). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with leucine at codon 616 of the RYR2 protein (p.Ser616Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. -

Oct 14, 2014

Blueprint Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 08, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The S616L variant has been reported previously as de novo in an adolescent female with syncopal spells during exercise, partly ectopic rhythm on ECG and polymorphic ventricular premature complexes on stress test (Marjamaa et al., 2009). This variant has also been found to have apparently occurred de novo in a child tested for arrhythmia at GeneDx; however, maternity and paternity testing was not performed. This variant was absent in 300 blood donors (Marjamaa et al., 2009) and was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S616L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and this substitution occurs at a position that is conserved across species. Consequently, in silico analysis predicts that S616L is damaging to the structure/function of the protein. However, the S616L variant is not 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).Therefore, this variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.8	D;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D;.
Polyphen		0.081	B;.
Vest4		0.95
MutPred		0.91		Loss of loop (P = 0.0374);.;
MVP		0.95
MPC		0.91
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.77
gMVP		0.85

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: rs730880187; hg19: chr1-237656273;