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

Total submissions: 4

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	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