ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.7111G>A (p.Glu2371Lys) (rs1057518940)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414976 SCV000492979 pathogenic Short stature; Delayed gross motor development; Congenital contracture; Proximal amyotrophy 2014-04-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198534 SCV001369509 pathogenic Short stature; Specific learning disability; Intellectual disability, mild; Delayed gross motor development; Intellectual disability, moderate; Congenital contracture; Proximal amyotrophy; Intellectual disability, severe 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. This variant was detected in heterozygous state.
Invitae RCV001233334 SCV001405922 likely pathogenic RYR1-Related Disorders 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2371 of the RYR1 protein (p.Glu2371Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of autosomal dominant RYR1-related myopathy (PMID: 29293505). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 374164). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant disrupts the p.Glu237 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19191333). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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