Submissions for variant NM_001035.3(RYR2):c.1250G>T (p.Arg417Leu)

dbSNP: rs751428303

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182679	SCV000235058	likely pathogenic	not provided	2013-06-04	criteria provided, single submitter	clinical testing	p.Arg417Leu (CGA>CTA): c.1250 G>T in exon 14 of the RYR2 gene (NM_001035.2). The Arg417Leu variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg417Leu results in a non-conservative amino acid substitution of a positively charged Arginine with a non-polar Leucine at a position that is conserved across species. In silico analysis predicts Arg417Leu is probably damaging to the protein structure/function. Arg417Leu is located in the N-terminal mutation hot spot" domain, and mutations in nearby residues (Arg414Cys, Arg414Leu, Thr415Arg, Ile419Phe) have been reported in association with CPVT, further supporting the functional importance of this region of the protein (Medeiros-Domingo A et al., 2009). Furthermore, Arg417Leu was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. With the clinical and molecular information available at this time, we cannot definitively determine if Arg417Leu is a disease-causing mutation or a rare benign variant. The variant is found in CPVT panel(s)."
Ambry Genetics	RCV002408797	SCV002669140	uncertain significance	Cardiovascular phenotype	2017-09-20	criteria provided, single submitter	clinical testing	The p.R417L variant (also known as c.1250G>T), located in coding exon 14 of the RYR2 gene, results from a G to T substitution at nucleotide position 1250. The arginine at codon 417 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.