ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1324G>T (p.Ala442Ser)

gnomAD frequency: 0.00003  dbSNP: rs747344666
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002537394 SCV000955844 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 442 of the RYR2 protein (p.Ala442Ser). This variant is present in population databases (rs747344666, gnomAD 0.006%). 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: 658546). 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 not expected to disrupt RYR2 protein function with a negative predictive value of 95%. 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 RCV001175924 SCV001339735 uncertain significance Cardiomyopathy 2023-05-10 criteria provided, single submitter clinical testing This missense variant replaces alanine with serine at codon 442 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 4/278742 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.
Ambry Genetics RCV003166343 SCV003868904 uncertain significance Cardiovascular phenotype 2022-11-29 criteria provided, single submitter clinical testing The p.A442S variant (also known as c.1324G>T), located in coding exon 15 of the RYR2 gene, results from a G to T substitution at nucleotide position 1324. The alanine at codon 442 is replaced by serine, an amino acid with similar properties. This amino acid position is poorly 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.

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