Submissions for variant NM_001035.3(RYR2):c.12056T>C (p.Met4019Thr)

dbSNP: rs886039150

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000249110	SCV000320350	uncertain significance	Cardiovascular phenotype	2019-08-02	criteria provided, single submitter	clinical testing	The p.M4019T variant (also known as c.12056T>C), located in coding exon 90 of the RYR2 gene, results from a T to C substitution at nucleotide position 12056. The methionine at codon 4019 is replaced by threonine, an amino acid with some similar properties. This alteration has been reported once in a 47-year-old male who died while sleeping and was overweight at 100 kg, 181 cm, with 780 g heart weight (Campuzano O et al. Forensic Sci. Int. 271;2017:120-125). This amino acid position is highly conserved in available vertebrate species, and is located within the C-terminal channel region, which is one of three regions of RYR2 that are enriched for mutations associated with CPVT (Medeiros-Domingo A. J Am Coll Cardiol. 2009 Nov; 54(22): 2065–2074). Internal structural analysis suggests that this alteration is moderately stabilizing in the closed-state structure; however, while there are no nearby pathogenic variants, it is more disruptive than more remote known pathogenic variants (Matera I. J Struct. Biol. 2010 Jun;170(3):548-64; Efremov RG. Nature. 2015 Jan;517(7532):39-43). In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
AiLife Diagnostics, AiLife Diagnostics	RCV000786206	SCV002502046	uncertain significance	not provided	2022-02-18	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786206	SCV000924926	uncertain significance	not provided	2017-01-18	no assertion criteria provided	provider interpretation