1-237454396-T-C

Variant names:

• chr1-237454396-T-C
• rs121918602
• NM_001035.3:c.1298T>C

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.1298T>C​(p.Leu433Pro) 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. L433F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 8.01

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 helix (size 27) in uniprot entity RYR2_HUMAN there are 16 pathogenic changes around while only 2 benign (89%) in NM_001035.3
• 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, 0.975
• PP5: Variant 1-237454396-T-C is Pathogenic according to our data. Variant chr1-237454396-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 12959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237454396-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.1298T>C	p.Leu433Pro	missense_variant	Exon 15 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.1298T>C	p.Leu433Pro	missense_variant	Exon 15 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.1298T>C		non_coding_transcript_exon_variant	Exon 15 of 104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.1298T>C	p.Leu433Pro	missense_variant	Exon 15 of 106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.1298T>C	p.Leu433Pro	missense_variant	Exon 15 of 105			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia Pathogenic:1

Feb 04, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu433Pro variant in RYR2 has been reported in 1 individual with ventricul ar arrhythmia, 1 individual with arrhythmogenic right ventricular dysplasia type 2 (ARVD2) and segregated with ARVD2 in 4 affected relatives from 1 family (Tiso 2001, Steriotis 2012). It has also been identified by our laboratory in 1 indiv idual with polymorphic ventricular bigeminy as well as in 2 family members with CPVT, 1 family member with history of cardiac arrest, and was absent in 6 unaffe cted relatives who were much older than the typical age of onset for CPVT. This variant was absent from large population studies and is listed in dbSNP without frequency information (rs121918602). Both in-vitro and in-vivo functional studie s have shown that the p.Leu433Pro variant impacts protein function (Thomas 2004, Jiang 2005, Tang 2012, and Shan 2012); however, these assays may not accurately represent biological function. In summary, this variant meets our criteria to b e classified as pathogenic for CPVT in an autosomal dominant manner (http://www. partners.org/personalizedmedicine/LMM) based upon segregation studies and absenc e from controls. -

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1

Feb 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardiovascular phenotype Pathogenic:1

Dec 26, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The RYR2 c.1298T>C (p.Leu433Pro) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found to be associated with reduced luminal Ca threshold at which Ca release terminates, desensitized caffeine-induced activation in HEK293 cells, increased diastolic SR Ca2+ leak in atrial myocytes (Tang_2012, Thomas_2004), and 37% AF occurrence in an in-vivo mouse model (Shan_2012). This variant is absent in 269324 control chromosomes in gnomAD and Tiso_2001. This variant was reported in multiple patients with ARVD (in a family where it segregated with disease)(Tiso_2001), CPVT, and LQTS (Steriotis_2012, Shigemizu_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Long QT syndrome Uncertain:1

-

Medical Research Institute, Tokyo Medical and Dental University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Benign	0.048
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;.
Polyphen		0.0060	B;.
Vest4		0.99
MutPred		0.92		Loss of helix (P = 0.0104);.;
MVP		0.94
MPC		1.3
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.93
gMVP		0.94

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: rs121918602; hg19: chr1-237617696;