ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4780G>A (p.Val1594Ile)

gnomAD frequency: 0.00001  dbSNP: rs794728737
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182727 SCV000235111 uncertain significance not provided 2012-06-04 criteria provided, single submitter clinical testing p.Val1594Ile (GTC>ATC): c.4780 G>A in exon 36 of the RYR2 gene (NM_001035.2). The Val1594Ile variant in the RYR2 gene has not been previously reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Val1594Ile results in a conservative amino acid substitution of one non-polar residue for another at a position that is not well-conserved in other species. In addition, the Val1594Ile variant is not located in any of the RYR2 mutation hot spots and no mutations in nearby codons have been reported, indicating this region may be tolerant of change (Medeiros-Domingo A et al., 2009). However, the NHLBI ESP Exome Variant Server reports Val1594Ile was not observed in approximately 5000 samples from individuals of European and African American backgrounds indicating it is not a common, benign variant in these populations. Therefore, the clinical significance of the Val1594Ile variant in the RYR2 gene is currently unknown. The variant is found in ARVC panel(s).
Color Diagnostics, LLC DBA Color Health RCV000778053 SCV000914168 uncertain significance Cardiomyopathy 2023-04-11 criteria provided, single submitter clinical testing This variant is located in the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/247702 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV003105815 SCV002239963 likely benign Catecholaminergic polymorphic ventricular tachycardia 1 2024-12-23 criteria provided, single submitter clinical testing

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