Submissions for variant NM_000540.3(RYR1):c.12083C>T (p.Ser4028Leu)

dbSNP: rs794728696

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000210653	SCV000262901	pathogenic	Inborn genetic diseases	2023-11-03	criteria provided, single submitter	clinical testing	The c.12083C>T (p.S4028L) alteration is located in coding exon 88 of the RYR1 gene. This alteration results from a C to T substitution at nucleotide position 12083, causing the serine (S) at amino acid position 4028 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been observed in multiple individuals with clinical features of RYR1-related myopathy, including several de novo occurrences (Dai, 2015; Kushnir, 2020; Biancalana, 2021). This amino acid position is highly conserved in available vertebrate species. Experimental evidence derived from studies on muscle biopsies of patients with the variant, demonstrated increased channel oxidation and reduced RyR1-calstabin1 binding, and increased sensitivity to Ca2+-dependent activation consistent with leaky channel behavior (Kushnir, 2020; Yuan, 2021). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000721259	SCV000335362	uncertain significance	not provided	2015-09-25	criteria provided, single submitter	clinical testing
Invitae	RCV000542897	SCV000659783	pathogenic	RYR1-related disorder	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 4028 of the RYR1 protein (p.Ser4028Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant congenital myopathy (PMID: 25987458, 27447704; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 201152). 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%. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000721259	SCV000852280	pathogenic	not provided	2021-10-04	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288788	SCV002579165	likely pathogenic	Central core myopathy	2022-04-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114333	SCV003800813	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2023-01-11	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.12083C>T (p.Ser4028Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251464 control chromosomes (gnomAD). c.12083C>T has been reported in the literature in multiple individuals affected with Congenital Myopathy and was shown to segregate with the disease in dominant families or to occur de novo in sporadic cases (e.g. Dai_2015, Kushnir_2020, Biancalana_2021, Natera-de Benito_2021). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant increased channel oxidation and reduced RyR1-calstabin1 binding, and was consistent with leaky channel behavior (Kushnir_2020, Yuan_2021). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000721259	SCV003812402	uncertain significance	not provided	2019-06-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147380	SCV003834842	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2021-02-10	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000721259	SCV005198093	pathogenic	not provided	2023-12-19	criteria provided, single submitter	clinical testing