rs1476195040

chr1-237456640-A-Cchr1-237456640-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2 PP3_Moderate

The NM_001035.3(RYR2):c.1517A>C(p.His506Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000824 in 1,456,452 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H506L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.56

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 3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.1517A>C	p.His506Pro	missense_variant	16/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.1517A>C	p.His506Pro	missense_variant	16/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.1517A>C	p.His506Pro	missense_variant	16/106
RYR2	ENST00000659194.3	c.1517A>C	p.His506Pro	missense_variant	16/105
RYR2	ENST00000609119.2	c.1517A>C	p.His506Pro	missense_variant, NMD_transcript_variant	16/104	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246442 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133666

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: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000824 AC: 12 AN: 1456452 Hom.: 0 Cov.: 39 AF XY: 0.00000690 AC XY: 5 AN XY: 724484

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000992

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

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

Dec 13, 2023

This missense variant replaces histidine with proline at codon 506 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 1/246442 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2021

The p.H506P variant (also known as c.1517A>C), located in coding exon 16 of the RYR2 gene, results from an A to C substitution at nucleotide position 1517. The histidine at codon 506 is replaced by proline, an amino acid with similar properties. This variant was reported in a cohort of individuals with suspected catecholaminergic polymorphic ventricular tachycardia (CPVT); however, clinical details were limited (Kapplinger JD et al. Circ Genom Precis Med, 2018 02;11:e001424). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	18
Dann	Benign	0.95
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.075
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.2	D;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0060	D;.
Polyphen		0.11	B;.
Vest4		0.72
MutPred		0.64		Gain of helix (P = 0.0225);.;
MVP		0.91
MPC		0.69
ClinPred		0.78	D
GERP RS		4.6
Varity_R		0.84
gMVP		0.87

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: rs1476195040; hg19: chr1-237619940;