ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
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 (; 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 Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000766712 SCV000554576 likely benign not provided 2019-02-22 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.