rs1060500136

chr1-237649922-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001035.3(RYR2):c.7558C>A(p.Leu2520Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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:4
• Conservation: PhyloP100: 2.12

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RYR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.34879005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.7558C>A	p.Leu2520Ile	missense_variant	50/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.7558C>A	p.Leu2520Ile	missense_variant	50/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.7558C>A	p.Leu2520Ile	missense_variant	50/106
RYR2	ENST00000659194.3	c.7558C>A	p.Leu2520Ile	missense_variant	50/105
RYR2	ENST00000609119.2	c.7558C>A	p.Leu2520Ile	missense_variant, NMD_transcript_variant	50/104	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

May 31, 2023

- -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 13, 2018

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 08, 2019

This sequence change replaces leucine with isoleucine at codon 2520 of the RYR2 protein (p.Leu2520Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Brugada syndrome (PMID: 25650408). ClinVar contains an entry for this variant (Variation ID: 404182). Algorithms developed to predict the effect of missense changes on protein structure and function 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2022

The p.L2520I variant (also known as c.7558C>A), located in coding exon 50 of the RYR2 gene, results from a C to A substitution at nucleotide position 7558. The leucine at codon 2520 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in a Brugada syndrome cohort (Le Scouarnec S et al. Hum Mol Genet, 2015 May;24:2757-63). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	19
Dann	Benign	0.95
DEOGEN2	Benign	0.41	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	0.98	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.3	N;.
REVEL	Uncertain	0.35
Sift	Benign	0.70	T;.
Polyphen		0.60	P;.
Vest4		0.50
MutPred		0.23		Gain of catalytic residue at L2525 (P = 0.0346);.;
MVP		0.63
MPC		0.73
ClinPred		0.89	D
GERP RS		3.5
Varity_R		0.14
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1060500136; hg19: chr1-237813222;