ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3971G>C (p.Gly1324Ala) (rs773678614)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000780693 SCV000918173 uncertain significance not specified 2017-10-23 criteria provided, single submitter clinical testing Variant summary: The RYR2 variant, c.3971G>C (p.Gly1324Ala), causes a missense change involving a non-conserved nucleotide and 3/4 in silico tools (SNPsandGO is not captured here due to low reliability index) predict a benign outcome. However, these predictions have not been functionally assessed. This variant was found in 7/276794 control chromosomes at a frequency of 0.0000253, which does not exceed the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000055). The variant has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories. Taken together, the variant has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171193 SCV001333888 uncertain significance Cardiomyopathy 2017-11-29 criteria provided, single submitter clinical testing
Color RCV001171193 SCV001344576 uncertain significance Cardiomyopathy 2019-12-30 criteria provided, single submitter clinical testing
Invitae RCV001210498 SCV001381988 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-09-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 1324 of the RYR2 protein (p.Gly1324Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs773678614, ExAC 0.001%). This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 632975). 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: "Benign"; Align-GVGD: "Class C55"). 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.

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