Submissions for variant NM_001035.3(RYR2):c.12271_12272delinsAG (p.Ala4091Arg)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182900	SCV000235289	pathogenic	not provided	2011-09-08	criteria provided, single submitter	clinical testing	This mutation is denoted Ala4091Arg (aka A4091R) at the protein level and c.12271_12272delinsAG at the cDNA level. A deletion of two nucleotides (GC) and insertion of two nucleotides (AG) was identified in exon 90 of the RYR2 gene. The sequence with the bases that are deleted in braces and inserted in brackets is: ACCT{GC}[AG]GAAG. The Ala4091Arg mutation has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. This mutation results in a non-conservative amino acid substitution of a non-polar Alanine with a positively charged Arginine. Ala4091Arg occurs in one of the three "hot-spot" domains where mutations are located throughout the RYR2 gene (Medeiros-Domingo A et al., 2009). In silico analysis predicts Ala4091Arg to be probably damaging to the protein structure/function (Adzhubei IA et al., 2010; Schwarz JM et al., 2011). Additionally, other mutations at this codon (Ala4091Val, Ala4091Thr) and in a nearby codon (Asn4097Ser) have been reported in association with CPVT and ventricular tachycardia (Hayashi M. et al., 2009), further supporting the functional importance of this position and region of the protein. Therefore, the presence of Ala4091Arg in the RYR2 gene is likely consistent with a diagnosis of CPVT. The variant is found in CPVT panel(s).
Invitae	RCV003638639	SCV001532881	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2020-02-22	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Ala4091 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19398665, 26132555, 26256814). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 201410). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with arginine at codon 4091 of the RYR2 protein (p.Ala4091Arg). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and arginine.

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