1-237806236-A-G

Variant names:

• chr1-237806236-A-G
• rs794728802
• NM_001035.3:c.14251A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_001035.3(RYR2):​c.14251A>G​(p.Lys4751Glu) 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. K4751Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.29
• Publications: 4 publications found

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]

RYR2 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 2

  Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-237806236-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 201355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia 2, arrhythmogenic right ventricular cardiomyopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863
• PP5: Variant 1-237806236-A-G is Pathogenic according to our data. Variant chr1-237806236-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 463577.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.14251A>G	p.Lys4751Glu	missense_variant	Exon 99 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.14251A>G	p.Lys4751Glu	missense_variant	Exon 99 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.14269A>G	p.Lys4757Glu	missense_variant	Exon 100 of 106			ENSP00000499393.2
RYR2	ENST00000609119.2	n.*5343A>G		non_coding_transcript_exon_variant	Exon 98 of 104	5		ENSP00000499659.2
RYR2	ENST00000609119.2	n.*5343A>G		3_prime_UTR_variant	Exon 98 of 104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 08, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

We consider the c.14251A>G (p.Lys4751Glu; p.K4751E) variant to be Likely Pathogenic, as it is present de novo in our affected patient and not present in his unaffected parents. The variant is absent from the gnomAD population dataset, despite reports of good sequencing coverage at this site. gnomAD (http://gnomad.broadinstitute.org) includes variant calls from 123,136 exome sequences and 15,496 genome sequences from unrelated individuals of non-Finnish European, Finnish, African, Latino, Ashkenazi Jewish, East Asian, and South Asian descent. gnomAD is comprised of multiple cohorts, some of which were recruited from the general population and others that include individuals sequenced as part of various disease-specific and population genetic studies; the phenotypes of individuals are not publicly available. The p.Lys4751Glu variant is novel. It has not been reported to date in the literature in any individuals with a RYR2-related disease, and it has not been submitted to ClinVar. However, a different variant at this same residue (p.Lys4751Gln; p.K4751Q) has been reported in one Japanese individual diagnosed with CPVT and atrial flutter (Kawamura et al., 2013). In ClinVar, the p.Lys4751Gln variant is classified as pathogenic by GeneDx as of 5/5/2014. In silico analysis programs (including PolyPhen, SIFT and MutationTaster) predict the p.Lys4751Glu variant to be damaging. The variant occurs at a residue that is highly conserved across vertebrate species and it is located in the channel region of the RYR2 gene, which is a known hotspot for mutations (Medeiros-Domingo A et al, 2009). Variants in nearby residues (p.His4742Tyr, p.His4762Pro) have been reported in the literature in association with sudden cardiac death and CPVT, respectively. Furthermore, variants in nearby residues (p.Val4760Ile, p.Asn4763Ser) have been reported to ClinVar as Likely Pathogenic, supporting the functional importance of this region of the protein. In summary, we consider this variant to be a rare missense change that is likely pathogenic. -

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1

Mar 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 4751 of the RYR2 protein (p.Lys4751Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 463577). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.82	L;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.3	D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0030	D;.
Polyphen		1.0	D;.
Vest4		0.71
MutPred		0.42		Loss of methylation at K4751 (P = 0.0083);.;
MVP		1.0
MPC		2.1
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.74
gMVP		0.95
Mutation Taster		=22/78	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs794728802; hg19: chr1-237969536;