rs397516508

Positions:

• chr1-237784256-G-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001035.3(RYR2):​c.12544G>C​(p.Glu4182Gln) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E4182A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 10.0

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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 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 chr1-237784257-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201335.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.
• 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, 0.846
• PP5: Variant 1-237784256-G-C is Pathogenic according to our data. Variant chr1-237784256-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.12544G>C	p.Glu4182Gln	missense_variant	90/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.12544G>C	p.Glu4182Gln	missense_variant	90/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.*3636G>C		non_coding_transcript_exon_variant	89/104	5		ENSP00000499659.2
RYR2	ENST00000609119.2	n.*3636G>C		3_prime_UTR_variant	89/104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 26, 2013

The Glu4182Gln variant in RYR2 has been identified by our laboratory in 1 Caucas ian child with CPVT, where it occurred de novo. This variant has not been seen i n large population studies. Computational analyses (biochemical amino acid prope rties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Glu4182Gln variant may impact the protein, though this information is not predictive enoug h to determine pathogenicity. In summary, all available data supports that the Glu4182Gln variant is likely pathogenic, but additional studies are needed to fu lly assess its clinical significance. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 27, 2013

p.Glu4182Gln (GAG>CAG): c.12544 G>C in exon 90 of the RYR2 gene (NM_001035.2). The Glu4182Gln variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The Glu4182Gln variant is a semi-conservative amino acid substitution as these residues share similar properties, but differ in size, charge, or other properties which may impact secondary structure. However, the Glu4182Gln residue is conserved across species. In silico analysis predicts Glu4182Gln is probably damaging to the protein structure/function. Mutations in nearby residues (Asn4178Tyr, Asn4178Ser, Glu4187Gln, and Leu4188Pro) have been reported in association with CPVT, further supporting the functional importance of this region of the protein. Glu4182Gln is located in the channel region, a mutation hotspot region of the RYR2 gene (Medeiros- Domingo A et al., 2009). Furthermore, the Glu4182Gln variant was not observed in approximately 6,000 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, while Glu4182Gln is a good candidate for a disease-causing mutation, we cannot unequivocally determine the clinical significance of this variant. The variant is found in CPVT panel(s). -

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 08, 2024

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative and gain of function are known mechanisms of disease in this gene and are associated with catecholaminergic polymorphic ventricular tachycardia 1 (MIM#604772) and left ventricular non-compaction (PMIDs: 12459180, 27646203, 29477366, 31875585, 33500567). Loss of function has been reported for ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (MIM#115000); however, a dominant negative mechanism has not been excluded (PMID: 33536282). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Penetrance for CPVT is estimated to be 60-70% (PMID: 23549275). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (PMID: 30696458). (SP) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. An alternative amino acid substitution at the same position, p.(Glu4182Ala), has been classified as a VUS and as likely pathogenic by clinical laboratories in ClinVar. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by clinical laboratories in ClinVar, with one entry reporting the variant as de novo in an individual with CPVT. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;T
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.5	D;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0050	D;.
Polyphen		1.0	D;.
Vest4		0.62
MutPred		0.28		Gain of methylation at K4183 (P = 0.0749);.;
MVP		0.96
MPC		1.9
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.46
gMVP		0.81

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: rs397516508; hg19: chr1-237947556; COSMIC: COSV100773463;