ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4273A>G (p.Thr1425Ala) (rs776046135)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV001093816 SCV000356283 uncertain significance Catecholaminergic polymorphic ventricular tachycardia type 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000295643 SCV000356284 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000389903 SCV000637563 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-12-14 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1425 of the RYR2 protein (p.Thr1425Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs776046135, ExAC 0.01%) but has not been reported in the literature in individuals with an RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 296724). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000618577 SCV000737882 uncertain significance Cardiovascular phenotype 2019-09-10 criteria provided, single submitter clinical testing Insufficient evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000994306 SCV001147759 uncertain significance not provided 2017-04-01 criteria provided, single submitter clinical testing
Color RCV001177868 SCV001342156 uncertain significance Cardiomyopathy 2020-01-15 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001199308 SCV001370388 uncertain significance Microcytic anemia; Hemolytic anemia; Cardiomyopathy; Hepatic failure; Hypochromic anemia; Elevated hepatic transaminases; Abnormality of mitochondrial metabolism; Abnormality of fatty-acid metabolism; Abnormality of carnitine metabolism 2019-04-30 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. This variant was detected in heterozygous state.

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