Submissions for variant NM_001035.3(RYR2):c.147G>C (p.Leu49Phe)

gnomAD frequency: 0.00004  dbSNP: rs727504508

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155648	SCV000205357	uncertain significance	not specified	2013-04-20	criteria provided, single submitter	clinical testing	The Leu49Phe variant in RYR2 has not been reported in individuals with cardiomyo pathy or in large population studies. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide st rong support for or against an impact to the protein. Additional studies are nee ded to fully assess the clinical significance of this variant.
Ambry Genetics	RCV000622773	SCV000741286	uncertain significance	Inborn genetic diseases	2016-02-01	criteria provided, single submitter	clinical testing
Invitae	RCV002514999	SCV000948647	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 49 of the RYR2 protein (p.Leu49Phe). This variant is not present in population databases (gnomAD no frequency). 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: 178876). 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) performed at Invitae indicates that this missense variant is expected to disrupt 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.
Color Diagnostics, LLC DBA Color Health	RCV001188624	SCV001355708	uncertain significance	Cardiomyopathy	2023-04-07	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 49 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 not been identified 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.
New York Genome Center	RCV001842487	SCV001468816	uncertain significance	Cardiac arrhythmia	2019-06-11	criteria provided, single submitter	clinical testing	The inherited c.147G>C (p.Leu49Phe) variant identified the RYR2 gene substitutes a highly conserved Leucine for Phenylalanine at amino acid 49/4968 (coding exon 2/105). This variant is absent from gnomAD and ExAC, suggesting it is not a common benign variant in the populations represented in these databases. In silico algorithms do not agree on the effect of this variant on the canonical transcript as it is predicted both Neutral (Provean; score: 0.69) and Damaging (SIFT; score: 0.000). It is reported twice in ClinVar as a Variant of Uncertain Significance (VarID: 178876), and to our current knowledge has not been identified in affected individuals in the literature. The Leu49 residue is located within the N-terminal region of RYR2, adjacent to the N-terminal domain, and varaints within this region have been implicated in cardiac arrhythmias [PMID: 17081562, PMID: 19926015].Given the lack of compelling evidence for the pathogenicity of the inherited c.147G>C (p.Leu49Phe) variant in RYR2, it is reported here as a Variant of Uncertain Significance.
Ambry Genetics	RCV002390356	SCV002699577	uncertain significance	Cardiovascular phenotype	2020-09-04	criteria provided, single submitter	clinical testing	The p.L49F variant (also known as c.147G>C), located in coding exon 2 of the RYR2 gene, results from a G to C substitution at nucleotide position 147. The leucine at codon 49 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available 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.