Submissions for variant NM_000540.3(RYR1):c.3964_3982dup (p.Asp1328fs)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487366	SCV000572591	likely pathogenic	not provided	2018-01-11	criteria provided, single submitter	clinical testing	The c.3964_3982dup19 variant causes a frameshift starting with codon Asparagine 1328, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Asp1328GlyfsX9. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.3964_3982dup19 variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although this variant has not been reported previously to our knowledge, other loss-of-function variants in the RYR1 gene have been reported in the Human Gene Mutation Database in association with RYR1-related disorders (Stenson et al., 2014).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380724	SCV001578876	pathogenic	RYR1-related disorder	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp1328Glyfs*9) 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 not present in population databases (gnomAD no frequency). 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: 422979). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000487366	SCV002019110	likely pathogenic	not provided	2019-02-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002481528	SCV002791329	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	2021-12-05	criteria provided, single submitter	clinical testing

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