Submissions for variant NM_000540.3(RYR1):c.7902C>A (p.Asn2634Lys)

gnomAD frequency: 0.00015  dbSNP: rs148041292

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000209968	SCV000265723	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000765449	SCV000896740	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000800203	SCV000939903	likely benign	RYR1-related disorder	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001356636	SCV003195002	uncertain significance	not provided	2022-07-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Revvity Omics, Revvity	RCV001356636	SCV003814436	uncertain significance	not provided	2023-10-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000209968	SCV004820931	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 2634 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown this variant increases sensitivity to RYR1-agonist 4-CmC when expressed in HEK293T cells compared to cells expressing wild-type RYR1 (PMID: 36208971). This variant has been reported in a family affected with malignant hyperthermia susceptibility (PMID: 36208971). This variant has been identified in 38/280230 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678749	SCV000804925	uncertain significance	not specified	2017-06-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356636	SCV001551860	uncertain significance	not provided		no assertion criteria provided	clinical testing	The RYR1 p.Asn2634Lys variant was not identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs148041292) Clinvitae, LOVD 3.0 and ClinVar (reported as a VUS by the Clinical Molecular Genetics Laboratory at John's Hopkins All Children's Hospital and by the ClinSeq Biesecker Lab at NIH for susceptibility to malignant hyperthermia). The variant was identified in control databases in 38 of 280230 chromosomes at a frequency of 0.000136 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 30 of 129078 chromosomes (freq: 0.000232), Latino in 7 of 35436 chromosomes (freq: 0.000198) and other in 1 of 7206 chromosomes (freq: 0.000139); it was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The RYR1 p.Asn2634Lys variant was found in an unaffected individual in a study analyzing 870 control participants for variants in genes related to malignant hyperthermia susceptibility (Gonsalves_2014_PMID: 24195946). The p.Asn2634 residue is not highly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.