1-237638480-G-C

Position:

• chr1-237638480-G-C

Variant summary

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

The ENST00000366574.7(RYR2):​c.6916G>C​(p.Val2306Leu) 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. V2306I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RYR2 ENST00000366574.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.99

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in ENST00000366574.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-237638480-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 201387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR2. . Gene score misZ 5.7809 (greater than the threshold 3.09). Trascript score misZ 6.4158 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.948
• PP5: Variant 1-237638480-G-C is Pathogenic according to our data. Variant chr1-237638480-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 201268.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.6916G>C	p.Val2306Leu	missense_variant	45/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.6916G>C	p.Val2306Leu	missense_variant	45/105	1	NM_001035.3	ENSP00000355533	P1
RYR2	ENST00000660292.2	c.6916G>C	p.Val2306Leu	missense_variant	45/106			ENSP00000499787
RYR2	ENST00000659194.3	c.6916G>C	p.Val2306Leu	missense_variant	45/105			ENSP00000499653
RYR2	ENST00000609119.2	c.6916G>C	p.Val2306Leu	missense_variant, NMD_transcript_variant	45/104	5		ENSP00000499659

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 18, 2013

p.Val2306Leu (GTC>CTC): c.6916 G>C in exon 45 of the RYR2 gene (NM_001035.2). While the Val2306Leu mutation in the RYR2 gene has not been published to our knowledge, a mutation affecting this same residue (Val2306Ile), has been reported as a de novo mutation in one individual diagnosed with CPVT (Laitinen P et al., 2003). Additionally, mutations in nearby residues (Glu2296Gln, Glu2311Asp, Ala2317Glu) have been reported in association with arrhythmia, further supporting the functional importance of the Val2306 residue and this region of the protein. Although Val2306Leu results in a conservative amino acid substitution of one non-polar amino acid for another, this substitution occurs at a position that is highly conserved across species, and is located in one of three mutation hot spot regions in the RYR2 gene (Medeiros-Domingo A et al., 2009). In silico analysis predicts Val2306Leu is damaging to the protein structure/function. Furthermore, Val2306Leu was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Val2306Leu in the RYR2 gene is interpreted as a likely disease-causing mutation. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is characterized by syncope, typically beginning in the first decade of life, which may be triggered by physical activity or intense emotion. In patients with CPVT, stress-induced release of catecholamines causes a dysfunction of the calcium--ion channel in the myocytes (De La Fuente et al., 2008; Napolitano C et al., 2012; Priori S et al., 2002). CPVT is primarily caused by autosomal dominant mutations in the RYR2 and KCNJ2 genes. Approximately 50% of patients with autosomal dominant CPVT have been reported to have a mutation in the RYR2 gene, while mutations in the RYR2 gene associated with ARVC are rare (McNally E et al., 2009; Napolitano C et al., 2012). The variant is found in ARVC,POSTMORTEM panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.7	D;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D;.
Polyphen		1.0	D;.
Vest4		0.72
MutPred		0.73		Loss of sheet (P = 0.0817);.;
MVP		0.97
MPC		1.1
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.70
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs794728746; hg19: chr1-237801780;