Submissions for variant NM_001035.3(RYR2):c.10046C>T (p.Ser3349Leu)

dbSNP: rs786205455

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000171173	SCV000221369	likely pathogenic	not provided		criteria provided, single submitter	research
Blueprint Genetics	RCV000208443	SCV000264188	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2015-03-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002470784	SCV000637468	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 3349 of the RYR2 protein (p.Ser3349Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with sudden death or dilated cardiomyopathy (PMID: 27650965, 28087566, 31931689). ClinVar contains an entry for this variant (Variation ID: 190999). 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) has been performed at Invitae 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000611661	SCV000732003	uncertain significance	not specified	2017-11-13	criteria provided, single submitter	clinical testing	The p.Ser3349Leu variant in RYR2 has been reported in 1 individual with sudden u nexplained death and 1 individual with sudden cardiac death (Christiansen 2016, Seidelmann 2017); however, both individuals carried an additional pathogenic var iant in a cardiomyopathy-associated gene. The p.Ser3349Leu variant was absent fr om large population studies. Computational prediction tools and conservation ana lysis suggest that the variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. In summary, the clinical sig nificance of the p.Ser3349Leu variant is uncertain. ACMG/AMP Criteria applied: P M2, PP3, BP5.
GeneDx	RCV000171173	SCV001766390	uncertain significance	not provided	2021-06-04	criteria provided, single submitter	clinical testing	Observed in an individual with dilated cardiomyopathy (Ramchand et al., 2020); Observed in individuals with sudden cardiac death; however, these individuals were also reported to have additional pathogenic variants in the TTN and DSP genes (Christiansen et al., 2016; Seidelmann et al., 2017); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID #190999; Landrum et al., 2016); Not 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19926015, 27650965, 26582918, 28087566, 31931689, 27535533)
Ambry Genetics	RCV002399612	SCV002707067	uncertain significance	Cardiovascular phenotype	2023-01-31	criteria provided, single submitter	clinical testing	The p.S3349L variant (also known as c.10046C>T), located in coding exon 69 of the RYR2 gene, results from a C to T substitution at nucleotide position 10046. The serine at codon 3349 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in two sudden unexplained death cases, both of which had additional cardiac variants detected (Christiansen SL et al. Eur. J. Hum. Genet., 2016 12;24:1797-1802; Seidelmann SB et al. Circ Cardiovasc Genet, 2017 Feb;10:[Epub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470784	SCV002768122	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. 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) (PMID: 12459180, 27646203, 29477366). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM and PMID: 22787013). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Two alternative amino acid changes at the same position have been observed in gnomAD (v2) (each present in 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as uncertain significance in ClinVar by clinical laboratories. It has also been reported as uncertain significance in two unrelated individuals who suffered a sudden death who also had additional protein truncating variants in the DSP and TTN genes, respectively (PMIDs: 27650965, 28087566). This variant has been observed in two additional individuals in our VCGS cohort - one with DCM and one who suffered a sudden death and had a family history of cardiomyopathy. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited [(LABID)]. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign