Submissions for variant NM_001035.3(RYR2):c.950T>C (p.Met317Thr)

gnomAD frequency: 0.00004  dbSNP: rs367601258

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522925	SCV000619988	uncertain significance	not provided	2017-08-14	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the RYR2 gene. Although the M317T variant has not been published in association with arrhythmia to our knowledge, it has been observed in at least one heterozygous individual from a cohort of patients referred for clinical whole exome sequencing (Landstrom et al., 2017); however, specific details regarding the indication for genetic testing or the patient's clinical phenotype were not described. This variant has also been observed in 1/9796 (0.010%) alleles from individuals of African ancestry, and in 3/66658 (0.005%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M317T 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. Furthermore, M317T is 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). However, although this substitution occurs at a position that is conserved in mammals, threonine (T) is the wild-type residue at this position in multiple non-mammalian species, Additionally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Ambry Genetics	RCV000620365	SCV000738244	uncertain significance	Cardiovascular phenotype	2020-09-30	criteria provided, single submitter	clinical testing	The p.M317T variant (also known as c.950T>C), located in coding exon 12 of the RYR2 gene, results from a T to C substitution at nucleotide position 950. The methionine at codon 317 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in an exome sequencing referral cohort, a sudden infant death syndrome cohort and a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10(4); Tester DJ et al. J. Am. Coll. Cardiol., 2018 03;71:1217-1227; van Lint FHM et al, 2019 Jun;27:304-309). This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV002525200	SCV000834414	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2023-12-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188885	SCV001356057	uncertain significance	Cardiomyopathy	2023-03-10	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 317 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden infant death syndrome (PMID: 29544605) and in another individual affected with unspecified arrhythmia (PMID: 30847666). This variant has been identified in 9/280154 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.
Fulgent Genetics, Fulgent Genetics	RCV002481717	SCV002789682	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-10-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000522925	SCV004224826	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing