Submissions for variant NM_001035.3(RYR2):c.1217C>T (p.Ser406Leu)

gnomAD frequency: 0.00002  dbSNP: rs759830423

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521452	SCV000617246	uncertain significance	not provided	2018-03-29	criteria provided, single submitter	clinical testing	The S406L variant in the RYR2 gene has been reported previously in an individual with familial catecholaminergic polymorphic ventricular tachycardia (CPVT); however, familial segregation information was not included (Jung et al., 2012). The S406L variant is observed in 2/18854 (0.012%) alleles from individuals of East Asian background and 5/276920 total alleles in large population cohorts (Lek et al., 2016). The S406L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret S406L as a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001190504	SCV001358007	uncertain significance	Cardiomyopathy	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 406 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study using a human stem cell-based model has shown that this variant affects calcium channel function, causing reduced sarcoplasmic reticulum Ca2+ content, delayed after-depolarization, and increased frequency and duration of Ca2+ release (PMID: 22174035). This variant has been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 22174035). This variant has been identified in 6/280428 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002525113	SCV002203259	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-12-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002481695	SCV002791290	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-09-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003599	SCV004844310	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 406 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study using a human stem cell-based model has shown that this variant affects calcium channel function, causing reduced sarcoplasmic reticulum Ca2+ content, delayed after-depolarization, and increased frequency and duration of Ca2+ release (PMID: 22174035). This variant has been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 22174035). This variant has been identified in 6/280428 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.
Ambry Genetics	RCV004984938	SCV005496956	uncertain significance	Cardiovascular phenotype	2024-11-21	criteria provided, single submitter	clinical testing	The p.S406L variant (also known as c.1217C>T), located in coding exon 14 of the RYR2 gene, results from a C to T substitution at nucleotide position 1217. The serine at codon 406 is replaced by leucine, an amino acid with dissimilar properties. This variant was detected in an 23 year old individual with sudden cardiac arrest and reported diagnosis of familial catecholaminergic polymorphic ventricular tachycardia (CPVT); however, additional clinical and segregation details were not provided (Jung CB et al. EMBO Mol Med, 2012 Mar;4:180-91). Studies performed on patient iPSC-derived cardiomyocytes have suggested this variant may impact calcium handling (Jung CB et al. EMBO Mol Med, 2012 Mar;4:180-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.