Submissions for variant NM_000540.3(RYR1):c.12951GCGGCGGCT[3] (p.4318RRL[3])

dbSNP: rs193922846

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000119470	SCV000575184	uncertain significance	not provided	2017-03-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000119470	SCV000852328	uncertain significance	not provided	2020-01-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000811546	SCV000951816	uncertain significance	RYR1-related disorder	2022-10-22	criteria provided, single submitter	clinical testing	This variant, c.12960_12968dup, results in the insertion of 3 amino acid(s) of the RYR1 protein (p.Arg4321_Leu4323dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with increased serum creatine kinase and malignant hyperthermia susceptibility (PMID: 16732084). This variant is also known as c.12959_12967dup, L4320_R4322dup. ClinVar contains an entry for this variant (Variation ID: 133044). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000119470	SCV001778002	uncertain significance	not provided	2024-07-16	criteria provided, single submitter	clinical testing	Reported (as c.12959_12967dup) in an individual with elevated creatine kinase levels and malignant hyperthermia susceptibility (PMID: 16732084); Identified with a second variant in an individual that died after being exposed to extreme heat for a significant amount of time (PMID: 19223216); In-frame insertion of 3 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23476141, 19223216, 16732084)
Fulgent Genetics, Fulgent Genetics	RCV002483205	SCV002785997	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-08-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000119470	SCV003802829	uncertain significance	not provided	2022-09-15	criteria provided, single submitter	clinical testing	The RYR1 c.12960_12968dup (p.Arg4321_Leu4323dup) variant results in a duplication of three amino acids in a non-repetitive region, arginine, arginine and leucine, at amino acid positions 4321, 4322 and 4323, respectively. This is an inframe event and is therefore predicted to preserve the reading frame. This variant is also referred to as c.12959_12967dup (p.Arg4320_Leu4322dup). The p.Arg4321_Leu4323dup has been reported in a heterozygous state in two individuals, an adult with elevated CK and an abnormal calcium-induced calcium release (CICR) test, and a child who expired following prolonged exposure to high temperature. However, neither were definitively diagnosed with malignant hyperthermia susceptibility at the time of reporting (PMID: 16732084; PMID: 19223216). The highest frequency of this allele in the Genome Aggregation Database is 0.000390 in the East Asian population (version 3.1.2). The p.Arg4321_Leu4323dup variant is in the CaM binding domain 3 (CaMBD3) of the RyR1 protein and isothermal titration calorimetry demonstrates that the variant results in altered binding between RyR1 and CaM, however the clinical implications of this finding are unclear (PMID: 24447242). Based on the available evidence, the c.12960_12968dup variant is classified as a variant of uncertain significance for malignant hyperthermia susceptibility.
Mayo Clinic Laboratories, Mayo Clinic	RCV000119470	SCV005408819	uncertain significance	not provided	2024-08-28	criteria provided, single submitter	clinical testing
Leiden Muscular Dystrophy (RYR1)	RCV000119470	SCV000154377	not provided	not provided		no assertion provided	not provided