Submissions for variant NM_001035.3(RYR2):c.11965A>C (p.Asn3989His)

dbSNP: rs794728779

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182803	SCV000235189	pathogenic	not provided	2014-12-09	criteria provided, single submitter	clinical testing	p.Asn3989His (AAT>CAT): c.11965 A>C in exon 90 of the RYR2 gene (NM_001035.2). The Asn3989His mutation in the RYR2 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Asn3989His results in a non-conservative amino acid substitution of a neutral, polar Asparagine with a positively charged Histidine at a residue that is conserved across species. The Asn3989His mutation is located in the channel region mutation hot spot, where other mutations in nearby codons (Met3978Ile, Val3990Asp) have been reported in association with CPVT (Medeiros-Domingo A et al., 2009). Additionally, a mutation at this codon (Asn3989Asp) has been seen as an apparently de novo mutation in one patient tested for arrhythmia at GeneDx, further supporting the functional importance of this codon. In summary, Asn3989His in the RYR2 gene is interpreted as a likely disease-causing mutation. The variant is found in CPVT panel(s).
Ambry Genetics	RCV003362716	SCV004054079	uncertain significance	Cardiovascular phenotype	2023-07-13	criteria provided, single submitter	clinical testing	The p.N3989H variant (also known as c.11965A>C), located in coding exon 90 of the RYR2 gene, results from an A to C substitution at nucleotide position 11965. The asparagine at codon 3989 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.