ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.10680T>A (p.His3560Gln) (rs727503404)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618121 SCV000737707 uncertain significance Cardiovascular phenotype 2016-09-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171684 SCV000055208 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000171684 SCV000235274 uncertain significance not provided 2018-11-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The H3560Q variant was reported as a variant of uncertain significance in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing (Ng et al., 2013). The H3560Q variant is observed in 14/26574 (0.01%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The H3560Q variant is not 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). Nonetheless, the H3560Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000688520 SCV000816136 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-09-24 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 3560 of the RYR2 protein (p.His3560Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. This variant is present in population databases (rs727503404, ExAC 0.008%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 165117). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151771 SCV000200189 uncertain significance not specified 2014-03-12 criteria provided, single submitter clinical testing The His3560Gln variant in RYR2 has been identified by our laboratory in 1 infant with DCM. It has also been detected in 1/948 chromosomes in a cohort that was not selected for cardiomyopathy by the ClinSeq study (Ng 2013). The affected ami no acid is conserved in evolution, suggesting that a change would not be tolerat ed. Other computational analyses do not provide strong support for or against a n impact to the protein. Additional information is needed to fully assess the cl inical significance of this variant.

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