rs121918603

Variant names:

• chr1-237639068-C-G
• rs121918603
• NM_001035.3:c.6982C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-237639068-C-G
• chr1-237639068-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001035.3(RYR2):​c.6982C>G​(p.Pro2328Ala) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2328L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.80

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 13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001035.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-237639068-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12960.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.959
• PP5: Variant 1-237639068-C-G is Pathogenic according to our data. Variant chr1-237639068-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 840374.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.6982C>G	p.Pro2328Ala	missense_variant	Exon 46 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.6982C>G	p.Pro2328Ala	missense_variant	Exon 46 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.6982C>G		non_coding_transcript_exon_variant	Exon 46 of 104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.6982C>G	p.Pro2328Ala	missense_variant	Exon 46 of 106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.6982C>G	p.Pro2328Ala	missense_variant	Exon 46 of 105			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1

Feb 10, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with alanine at codon 2328 of the RYR2 protein (p.Pro2328Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of catecholaminergic polymorphic ventricular tachycardia (Invitae. In at least one individual the variant was observed to be de novo. 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 disrupts the p.Pro2328 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been observed in individuals with RYR2-related conditions (PMID: 15197150), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.3	D;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.78		Gain of MoRF binding (P = 0.0427);.;
MVP		0.82
MPC		1.1
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.82
gMVP		0.83

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: rs121918603; hg19: chr1-237802368;