ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.36G>C (p.Gln12His)

gnomAD frequency: 0.00002  dbSNP: rs746811389
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003103817 SCV000760591 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 12 of the RYR2 protein (p.Gln12His). This variant is present in population databases (rs746811389, gnomAD 0.01%). 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: 532322). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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 RCV000773022 SCV000906404 uncertain significance Cardiomyopathy 2023-06-16 criteria provided, single submitter clinical testing This variant is located in 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 been identified in 3/39990 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 RCV002343256 SCV002621892 uncertain significance Cardiovascular phenotype 2021-03-30 criteria provided, single submitter clinical testing The p.Q12H variant (also known as c.36G>C), located in coding exon 1 of the RYR2 gene, results from a G to C substitution at nucleotide position 36. The glutamine at codon 12 is replaced by histidine, an amino acid with highly similar properties. This variant was reported in a whole exome sequencing cohort; however, clinical details were limited (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:). 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.

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