ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.2935G>T (p.Ala979Ser) (rs202015519)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154816 SCV000204497 uncertain significance not specified 2013-10-10 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Ala979Ser varia nt in RYR2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.2% (9/3790) African American chromosomes by the NHL BI Exome Sequenicng Project (http://evs.gs.washington.edu; dbSNP rs202015519). A lanine (Ala) at position 979 is conserved in mammals and across most evolutionar y distant species, although 1 fish (lamprey) has a serine (Ser; this variant) at this position, raising the possibility that this change may be tolerated. Addit ional computational analyses (biochemical amino acid properties, AlignGVGD, Poly Phen2, and SIFT) do not provide strong support for or against an impact to the n ormal function of the protein. While the frequency of this variant suggests that it is more likely benign, it is too low to confidently rule out a disease-causi ng role. Additional information is needed to fully assess its clinical significa nce.
GeneDx RCV000766712 SCV000235085 uncertain significance not provided 2018-07-31 criteria provided, single submitter clinical testing The A979S variant of uncertain significance in the RYR2 gene has been reported previously in one individual with HCM (Lopes et al., 2015). Additionally, A979S was identified in a clinical whole exome sequencing cohort assessed for incidental CPVT-associated variants; authors classified A979S as a variant of uncertain clinical significance (Landstrom et al., 2017). Neither of these publications included patient-specific clinical data. This variant has been identified both independently of and in conjunction with additional cardiogenetic variants in multiple individuals referred for cardiomyopathy genetic testing at GeneDx. The A979S variant has also been observed in 39/24,004 (0.16%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). The A979S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, A979S 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).
Ambry Genetics RCV000246594 SCV000320112 uncertain significance Cardiovascular phenotype 2018-04-25 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV001080003 SCV000554576 likely benign Catecholaminergic polymorphic ventricular tachycardia 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001100557 SCV001257082 benign Catecholaminergic polymorphic ventricular tachycardia type 1 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001100558 SCV001257083 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color RCV001178122 SCV001342479 likely benign Cardiomyopathy 2018-12-17 criteria provided, single submitter clinical testing

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