Submissions for variant NM_000540.3(RYR1):c.14809A>G (p.Ile4937Val)

dbSNP: rs2145917369

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282528	SCV002571990	uncertain significance	not specified	2022-08-12	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.14809A>G (p.Ile4937Val) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251464 control chromosomes (gnomAD). To our knowledge, no occurrence of c.14809A>G in individuals affected with Malignant Hyperthermia Susceptibility has been published in the literature, however a ClinVar submission described a variant carrier, who suffered a malignant hyperthermia event after the administration of anesthetic, and her father (also a carrier) presented with an idiopathic CK elevation. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated a significant increase in Ca2+ release in response to a RYR1 agonist (caffeine) in an in vitro transfection assay (HEK293), where Ca2+ release was measured by fluorescence; these results are consistent with a gain of function mechanism, characteristic for malignant hyperthermia susceptibility (MHS; see PMID: 33767344). In addition, neighboring missense changes (Gly4935Asp/Ser, Leu4936Arg, Ile4938Met/Thr/Val, and Asp4939Glu) are reported in affected individuals (with varying phenotypes), indicating a functional significance for this protein region (HGMD). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
HUSP Clinical Genetics Laboratory, Hospital Universitario San Pedro De Logroño (HUSP)	RCV001353219	SCV001547261	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2019-10-16	no assertion criteria provided	clinical testing	The c.14809A>G variant, located in coding exon 102 of the RYR1 gene (NM_000540.3), results from a A to G substitution at nucleotide position 14809. The isoleucine at codon 4937 is replaced by valine. This alteration has not been reported previously in the literature and it is not detected in general population. The amino acid position is conserved in available vertebrate species and in-silico tools predict that it is very likely to affect protein function. Pathological variants in the RYR1 gene are associated with the phenotype of Malignant hyperthermia susceptibility 1 (OMIM: 145600) with autosomal dominant inheritance. The alteration was detected in a 6-year-old girl who suffered a malignant hyperthermia event after the administration of anesthetic. The variant was detected in her father (presented an idiopathic elevation of CK) and her 9-year-old sister. Therefore, we consider that clinical significance of c.14809A>G variant is likely pathogenic.