1-237709081-A-G

Position:

• chr1-237709081-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001035.3(RYR2):​c.10125A>G​(p.Arg3375=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,433,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: RYR2 NM_001035.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.28

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 1-237709081-A-G is Benign according to our data. Variant chr1-237709081-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235051.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
• BS2: High AC in GnomAdExome4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.10125A>G	p.Arg3375=	synonymous_variant	69/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.10125A>G	p.Arg3375=	synonymous_variant	69/105	1	NM_001035.3	ENSP00000355533	P1
RYR2	ENST00000660292.2	c.10125A>G	p.Arg3375=	synonymous_variant	69/106			ENSP00000499787
RYR2	ENST00000659194.3	c.10125A>G	p.Arg3375=	synonymous_variant	69/105			ENSP00000499653
RYR2	ENST00000609119.2	c.*1160A>G		3_prime_UTR_variant, NMD_transcript_variant	67/104	5		ENSP00000499659

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000874 AC: 2 AN: 228944 Hom.: 0 AF XY: 0.00000803 AC XY: 1 AN XY: 124496

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000187

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000279 AC: 40 AN: 1433284 Hom.: 0 Cov.: 30 AF XY: 0.0000254 AC XY: 18 AN XY: 709962

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000346

Gnomad4 OTH exome AF: 0.0000339

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jan 21, 2014

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. 61yo Caucasian male with ARVC. Genetic testing: The patient had genetic testing with the GeneDx laboratory with their comprehensive cardiomyopathy panel. This was ordered by his PAMF cardiologist, Dr. Aria Dibiase. The test included 77 genes associated with various hereditary cardiomyopathies: ABCC9, ACTC (ACTC1), ACTN2, ANKRD1, BAG3, BRAF, CAV3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL, NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43,TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. Analysis included both sequencing and array-based comparative genome hybridization to look for duplications and deletions (excluding mitochondrial genes, FKTN, GATAD1) Results reported on June 9th, 2015 showed the following variants were found (see report below): -p.Glu102Lys (c.304G>A) in the DSC2 gene (NM_024422.3) -p.Arg3375Arg (c.10125A>G) in the RYR2 gene (NM_001035.2) -p.Ala551Val (c.1652C>T) in the LAMA4 gene (NM_002290.3) These variants are reviewed in detail below. They are all inconclusive. The DSC2 variant is likely too common to cause ARVC. There is minimal data available on the other two genes. Given the large number of genes included on this panel and the large and variable nature of some of these genes, it is expected that most individuals (including individuals who don't have inherited cardiac disease) would have at least one and several rare variants found with this test. As a result it is important to consider the data available on each variant to determine whether it is a disease-predisposing variant or one of the many benign rare variants that we all have. p.Glu102Lys (c.304G>A) in the DSC2 gene (NM_024422.3) GeneDx classifies this variant as a "variant, likely disease causing", which, per prior discussion with them, is equivalent to a variant of uncertain significance, probably disease causing. Given the variant has been observed in disparate phenotypes and is present with an MAF >0.1% in samples unselected for ARVC, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Per the GeneDx report and the LMM ClinVar entry, the variant has been reported in the literature in at least 5 individuals with ARVC (Beffagna 2007, De Bertoli et al 2010, Quarta 2011, Anastasakis 2012). Assertions in ClinVar are conflicting with variant of uncertain significance (LMM, Blueprint), likely benign (CSER), likely pathogenic (GeneDx). In their ClinVar submission, LMM notes that they have observed this variant in 6 individuals with varied phenotypes: "1 with SCA, 1 with HCM, 1 with ARVC and 3 with DCM (1 of whom carries likely pathogenic variant in MYBPC3)." p.Arg3375Arg (c.10125A>G) in the RYR2 gene (NM_001035.2) Given The lack of case data and unclear role of variants of this type in this gene, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant appears to be novel. The variant is predicted to create a cryptic splice donor site in exon 69 that is predicted to cause abnormal gene splicing. However, they note that only one splice variant in RYR2 is reported in HGMD in association with CPVT. There are only four splicing variants in RYR2 in ClinVar. Three are noted as variant -

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 11, 2024

This synonymous variant causes a nucleotide substitution but does not change the encoded amino acid at codon 3375 of the RYR2 protein. Splice prediction tools are inconclusive regarding the impact of this variant on RNA splicing. 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 2/228944 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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 12, 2019

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; 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.; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 235051; Landrum et al., 2016) -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 04, 2023

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.45		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs764396074; hg19: chr1-237872381;