Submissions for variant NM_000540.3(RYR1):c.11763C>A (p.Tyr3921Ter)

gnomAD frequency: 0.00004  dbSNP: rs377178986

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704053	SCV000832986	pathogenic	RYR1-related disorder	2023-07-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr3921*) in the RYR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RYR1 are known to be pathogenic (PMID: 23919265, 25960145, 28818389, 30611313). This variant is present in population databases (rs377178986, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with autosomal recessive RYR1-related conditions (PMID: 22473935, 28818389). ClinVar contains an entry for this variant (Variation ID: 161361). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000721251	SCV000852268	pathogenic	not provided	2019-10-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478416	SCV000894193	likely pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2022-04-11	criteria provided, single submitter	clinical testing
Mendelics	RCV000990206	SCV001141073	pathogenic	Malignant hyperthermia, susceptibility to, 1	2022-05-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001266922	SCV001445103	pathogenic	Inborn genetic diseases	2017-12-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001795258	SCV001774653	pathogenic	Congenital myopathy with fiber type disproportion	2021-07-08	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.11763C>A (p.Tyr3921X) results in a premature termination codon, experimentally demonstrated to lead to absence of transcription (and therefore of the protein) (Zhou_2006, Klein_2012) due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 2.4e-05 in 251492 control chromosomes (gnomAD). c.11763C>A has been reported in the literature in individuals affected with autosomal recessive RYR1-related myopathy (e.g. Klein_2012, Amburgey_2013). These data indicate that the variant is likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and one ClinVar submitter (evaluation after 2014) cites it as benign. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000721251	SCV002019102	likely pathogenic	not provided	2021-11-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000721251	SCV003805531	pathogenic	not provided	2023-02-24	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25637381, 28818389, 32721234, 25683120, 22473935, 23553484)
CSER _CC_NCGL, University of Washington	RCV000148788	SCV000190526	likely benign	Congenital myopathy	2014-06-01	no assertion criteria provided	research