Submissions for variant NM_001035.3(RYR2):c.14623G>C (p.Asp4875His)

dbSNP: rs794728806

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182848	SCV000235236	likely pathogenic	not provided	2014-01-16	criteria provided, single submitter	clinical testing	p.Asp4875His (GAC>CAC): c.14623 G>C in exon 102 of the RYR2 gene (NM_001035.2). The D4875H variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The D4875H variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The D4875 residue is highly conserved across species, and D4875H is located in the mutation hotspot channel region of the RYR2 gene (Medeiros-Domingo A et al., 2009). Mutations in nearby residues (L4865V, I4867M, V4880A) have been reported in association with arrhythmia, further supporting the functional importance of this region of the protein. In silico analysis predicts D4875H is damaging to the protein structure/function. Furthermore, the D4875H variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, while D4875H is a good candidate for a disease-causing mutation, we cannot unequivocally determine the clinical significance of this variant. The variant is found in ARRHYTHMIA panel(s).