Submissions for variant NM_001035.3(RYR2):c.14167G>A (p.Ala4723Thr)

gnomAD frequency: 0.00003  dbSNP: rs397516514

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036693	SCV000060348	uncertain significance	not specified	2011-12-21	criteria provided, single submitter	clinical testing	The Ala4723Thr variant (RYR2) has not been previously reported not previously id entified by our laboratory. Alanine (Ala) is moderately conserved across evoluti onarily distant species (frog has a valine (Val) at this position), and this inf ormation is insufficient to predict if a change would impact the protein. Comput ational predictions on the impact to the protein are mixed (AlignGVGD = benign, PolyPhen2 & SIFT = pathogenic), though the accuracy of these tools is unknown. A dditional information is needed to fully assess the clinical significance of the Ala4723Thr variant.
Color Diagnostics, LLC DBA Color Health	RCV001175858	SCV001339637	uncertain significance	Cardiomyopathy	2023-01-10	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 4723 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 cardiovascular disorders in the literature. This variant has been identified in 7/280352 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.
GeneDx	RCV001797049	SCV002038586	uncertain significance	not provided	2023-09-25	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); This variant is associated with the following publications: (PMID: 19926015)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513407	SCV002114844	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-06-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162319	SCV003911260	uncertain significance	Cardiovascular phenotype	2022-11-15	criteria provided, single submitter	clinical testing	The c.14167G>A (p.A4723T) alteration is located in exon 99 (coding exon 99) of the RYR2 gene. This alteration results from a G to A substitution at nucleotide position 14167, causing the alanine (A) at amino acid position 4723 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV003996256	SCV004822283	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 4723 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 cardiovascular disorders in the literature. This variant has been identified in 7/280352 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.