Submissions for variant NM_001035.3(RYR2):c.13237C>A (p.Pro4413Thr)

gnomAD frequency: 0.00006  dbSNP: rs773441342

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520156	SCV000619185	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); This variant is associated with the following publications: (PMID: 19926015)
Color Diagnostics, LLC DBA Color Health	RCV001180380	SCV001345300	uncertain significance	Cardiomyopathy	2023-11-17	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 4413 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). 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 2/31386 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293463	SCV001482033	uncertain significance	not specified	2021-02-22	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.13237C>A (p.Pro4413Thr) results in a non-conservative amino acid change located in the Ryanodine Receptor TM 4-6 domain (IPR009460) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-06 in 219054 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.13237C>A in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002527613	SCV002140356	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002384009	SCV002691424	uncertain significance	Cardiovascular phenotype	2020-06-09	criteria provided, single submitter	clinical testing	The p.P4413T variant (also known as c.13237C>A), located in coding exon 90 of the RYR2 gene, results from a C to A substitution at nucleotide position 13237. The proline at codon 4413 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004003613	SCV004824195	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 4413 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/250440 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.