ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.458C>T (p.Thr153Ile) (rs766802574)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182656 SCV000235034 uncertain significance not provided 2017-04-05 criteria provided, single submitter clinical testing The Thr153Ile variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Thr153Ile results in a non-conservative amino acid substitution of a polar Threonine residue with a non-polar Isoleucine at a position that is conserved in mammals and chicken. In silico analysis predicts Thr153Ile is possibly damaging to the protein structure/function. Also, the NHLBI ESP Exome Variant Server reports Thr153Ile was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby codons have been reported in association with an RYR2-related phenotype, indicating this region of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if Thr153Ile is a disease-causing mutation or a rare benign variant.
Invitae RCV000806084 SCV000946065 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-10-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 153 of the RYR2 protein (p.Thr153Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs766802574, ExAC 0.004%). This variant has been observed in individuals affected with sudden arrhythmic death syndrome (PMID: 28449774). ClinVar contains an entry for this variant (Variation ID: 201192). 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 C65"). 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 RCV001186488 SCV001352924 uncertain significance Cardiomyopathy 2019-09-09 criteria provided, single submitter clinical testing

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