Submissions for variant NM_001035.3(RYR2):c.11995A>T (p.Met3999Leu)

dbSNP: rs794728780

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182890	SCV000235279	pathogenic	not provided	2011-11-08	criteria provided, single submitter	clinical testing	This variant is denoted Met3999Leu (aka M3999L) at the protein level and c.11995 A>T at the cDNA level. An A>T nucleotide substitution was identified in exon 90 of the RYR2 gene, resulting in replacement of the normal Methionine codon (ATG) with a Leucine codon (TTG) at amino acid position 3999 in the cardiac ryanodine receptor. The Met3999Leu variant in the RYR2 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Although Met3999Leu results in a conservative amino acid substitution of one non-polar amino acid for another, the Met3999 residue is conserved across species. In addition, Met3999Leu is located in a mutation hot spot within the channel region of the RYR2 gene (Medeiros-Domingo A et al., 2009). Mutations in nearby codons (Val3990Asp, Lys3997Glu) have been reported in association with CPVT, further supporting the functional importance of this region of the protein. Furthermore, another missense change at this codon (Met3999Val) was identified as a de novo disease-causing mutation in other individuals tested for CPVT at GeneDx. Met3999Leu was not observed in up to 200 control alleles from individuals of African American ancestry tested at GeneDx, indicating it is not a common benign variant in this population. This variant has been observed de novo without confirmed parentage. The variant is found in CPVT panel(s).