Submissions for variant NM_001035.3(RYR2):c.2717C>T (p.Pro906Leu)

gnomAD frequency: 0.00006  dbSNP: rs397516522

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036719	SCV000060374	uncertain significance	not specified	2013-05-03	criteria provided, single submitter	clinical testing	The Pro906Leu variant in RYR2 has been identified by our laboratory in 1 Caucasi an individual with HCM, but was not identified in large population studies. Comp utational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to t he protein. In addition, this variant is located in the last three bases of the exon, which is part of the 5? splice region. Computational tools do not suggest an impact to splicing, though this information is not predictive enough to rule out pathogenicity. In summary, additional information is needed to fully assess the clinical significance of this variant.
Invitae	RCV001097007	SCV000831731	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 906 of the RYR2 protein (p.Pro906Leu). This variant is present in population databases (rs397516522, gnomAD 0.02%). 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: 43760). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Color Diagnostics, LLC DBA Color Health	RCV000777966	SCV000914067	uncertain significance	Cardiomyopathy	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 906 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 not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 9/279776 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.
Illumina Laboratory Services, Illumina	RCV001097006	SCV001253257	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2019-10-18	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001097007	SCV001253258	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2019-10-18	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.