chr1-237042557-G-C

Variant names:

• chr1-237042557-G-C
• rs746811389
• NM_001035.3:c.36G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP2 BS1_Supporting BS2

The NM_001035.3(RYR2):​c.36G>C​(p.Gln12His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,261,812 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Q12Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.650
• Publications: 1 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_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_001035.3
• 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.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000144 (16/1109710) while in subpopulation MID AF = 0.000219 (1/4566). AF 95% confidence interval is 0.0000172. There are 0 homozygotes in GnomAdExome4. There are 11 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.36G>C	p.Gln12His	missense	Exon 1 of 105	NP_001026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.36G>C	p.Gln12His	missense	Exon 1 of 105	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.36G>C	p.Gln12His	missense	Exon 1 of 106	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.36G>C		non_coding_transcript_exon	Exon 1 of 104	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152102 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000750 AC: 3 AN: 39990 AF XY: 0.0000497

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000147

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 16 AN: 1109710 Hom.: 0 Cov.: 31 AF XY: 0.0000209 AC XY: 11 AN XY: 525762

African (AFR) AF: 0.00 AC: 0 AN: 23608

American (AMR) AF: 0.00 AC: 0 AN: 9732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14506

East Asian (EAS) AF: 0.00 AC: 0 AN: 27476

South Asian (SAS) AF: 0.0000979 AC: 2 AN: 20430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37062

Middle Eastern (MID) AF: 0.000219 AC: 1 AN: 4566

European-Non Finnish (NFE) AF: 0.0000140 AC: 13 AN: 927776

Other (OTH) AF: 0.00 AC: 0 AN: 44554

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152102 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74288

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000926 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiovascular phenotype Uncertain:2

Mar 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q12H variant (also known as c.36G>C), located in coding exon 1 of the RYR2 gene, results from a G to C substitution at nucleotide position 36. The glutamine at codon 12 is replaced by histidine, an amino acid with highly similar properties. This variant was reported in a whole exome sequencing cohort; however, clinical details were limited (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Mar 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/39990 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Cardiomyopathy Uncertain:1

Jun 16, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 3/39990 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 12 of the RYR2 protein (p.Gln12His). This variant is present in population databases (rs746811389, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 532322). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.84	D
Eigen	Benign	0.18
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	1.7	L
PhyloP100		0.65
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.76
Sift	Uncertain	0.017	D
Polyphen		0.98	D
Vest4		0.35
MutPred		0.56		Gain of sheet (P = 0.039)
MVP		0.82
MPC		0.70
ClinPred		0.24	T
GERP RS		2.3
PromoterAI		0.19	Neutral
Varity_R		0.35
gMVP		0.21
Mutation Taster		=59/41	polymorphism

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: rs746811389; hg19: chr1-237205857;