Submissions for variant NM_001035.3(RYR2):c.12372C>A (p.Ser4124Arg)

dbSNP: rs771994461

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182816	SCV000235202	pathogenic	not provided	2012-06-05	criteria provided, single submitter	clinical testing	p.Ser4124Arg (AGC>AGA): c.12372 C>A in exon 90 of the RYR2 gene (NM_001035.2). The Ser4124Arg mutation in the RYR2 gene has not been reported previously as a disease-causing mutation, nor as a benign polymorphism, to our knowledge. Ser4124Arg results in a semi-conservative amino acid substitution of a neutral, polar Serine residue with a positively charged Arginine residue. Located in the cytoplasmic I-domain RYR2 mutation hot spot, mutations at the same residue (Ser4124Gly, Ser4124Thr) as well as a nearby residue (Arg4144Cys) have been reported in association with CPVT, supporting the functional importance of this region of the protein. In addition, the NHLBI ESP Exome Variant Server reports Ser4124Arg was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, Ser4124Arg in the RYR2 gene is interpreted to be a likely disease-causing mutation. The variant is found in CPVT panel(s).
Invitae	RCV002517801	SCV001576445	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 4124 of the RYR2 protein (p.Ser4124Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with catecholaminergic polymorphic ventricular tachycardia (PMID: 23595086; Invitae). ClinVar contains an entry for this variant (Variation ID: 201330). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. This variant disrupts the p.Ser4124 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been observed in individuals with RYR2-related conditions (PMID: 19330009, 26114861), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.