Submissions for variant NM_000540.3(RYR1):c.11023G>C (p.Asp3675His)

gnomAD frequency: 0.00004  dbSNP: rs145026307

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198050	SCV001368835	uncertain significance	Congenital myopathy with fiber type disproportion	2019-06-06	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001863120	SCV002156386	uncertain significance	RYR1-related disorder	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 3675 of the RYR1 protein (p.Asp3675His). This variant is present in population databases (rs145026307, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 931477). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR1 protein function with a negative predictive value of 95%. 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002224019	SCV002503537	uncertain significance	not provided	2020-12-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504224	SCV002814379	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	2021-07-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV002224019	SCV004236896	uncertain significance	not provided	2023-07-25	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV002224019	SCV005196818	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing