rs1431073529

Variant names:

• chr1-237369546-G-A
• rs1431073529
• NM_001035.3:c.322G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-237369546-G-A
• chr1-237369546-G-C
• chr1-237369546-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2 BS2

The NM_001035.3(RYR2):​c.322G>A​(p.Gly108Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000134 in 1,562,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 6.75
• 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 -3 ACMG points.

• 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.
• BS2: High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.322G>A	p.Gly108Ser	missense_variant	Exon 6 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.322G>A	p.Gly108Ser	missense_variant	Exon 6 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.322G>A	p.Gly108Ser	missense_variant	Exon 6 of 106			ENSP00000499393.2
RYR2	ENST00000609119.2	n.322G>A		non_coding_transcript_exon_variant	Exon 6 of 104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000227 AC: 4 AN: 176116 AF XY: 0.0000108

Gnomad AFR exome AF: 0.0000982

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: 0.0000279

Gnomad OTH exome AF: 0.000210

GnomAD4 exome AF: 0.0000128 AC: 18 AN: 1410732 Hom.: 0 Cov.: 30 AF XY: 0.0000129 AC XY: 9 AN XY: 696594

African (AFR) AF: 0.00 AC: 0 AN: 32336

American (AMR) AF: 0.0000269 AC: 1 AN: 37192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25310

East Asian (EAS) AF: 0.00 AC: 0 AN: 37346

South Asian (SAS) AF: 0.00 AC: 0 AN: 79946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50390

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5714

European-Non Finnish (NFE) AF: 0.0000148 AC: 16 AN: 1083962

Other (OTH) AF: 0.00 AC: 0 AN: 58536

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74298

African (AFR) AF: 0.0000241 AC: 1 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Nov 18, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RYR2 c.322G>A (p.Gly108Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 176116 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.322G>A has been reported in the literature in at-least one individual affected withdilated cardiomyopathy, however this individual also had a co-occurrence in TTN gene (c.81341dup) (Kolokotronis_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32659924). ClinVar contains an entry for this variant (Variation ID: 463594). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Dec 01, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with serine at codon 108 of 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 been reported in an individual affected with dilated cardiomyopathy and arrhythmia, who also carried a truncating variant in the TTN gene (PMID: 32659924). This variant has been identified in 4/176116 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

Aug 09, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with serine at codon 108 of 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 been reported in an individual affected with dilated cardiomyopathy and arrhythmia, who also carried a truncating variant in the TTN gene (PMID: 32659924). This variant has been identified in 4/176116 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. -

not provided Uncertain:1

Dec 10, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance by another clinical laboratory (ClinVar Variant ID#463594; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009) -

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 108 of the RYR2 protein (p.Gly108Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 463594). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Possibly Damaging". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -

Cardiovascular phenotype Uncertain:1

May 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G108S variant (also known as c.322G>A), located in coding exon 6 of the RYR2 gene, results from a G to A substitution at nucleotide position 322. The glycine at codon 108 is replaced by serine, an amino acid with similar properties. This amino acid position is well 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.1	M;.
PhyloP100		6.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Pathogenic	0.72
Sift	Benign	0.49	T;.
Polyphen		1.0	D;.
Vest4		0.35
MutPred		0.45		Loss of helix (P = 0.0196);.;
MVP		0.94
MPC		0.70
ClinPred		0.94	D
GERP RS		4.5
Varity_R		0.43
gMVP		0.42
Mutation Taster		=14/86	disease causing

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: rs1431073529; hg19: chr1-237532846;