ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.14672G>A (p.Gly4891Asp) (rs398123470)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000493428 SCV000111002 uncertain significance not provided 2018-09-06 criteria provided, single submitter clinical testing
GeneDx RCV000493428 SCV000582008 likely pathogenic not provided 2015-08-25 criteria provided, single submitter clinical testing The G4891D variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. However, another variant at the same amino acid position, G4891R, has been reported in an individual with Central Core disease (Tilgen et al., 2001). Electrophysiological studies showed that G4891R (referred to as G4890R), and mutations in exon 102, resulted in reduced voltage-gated calcium release in comparison to wildtype (Avila et al., 2003). G4891D was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G4891D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and predicted to be located within the pore forming unit of the channel. Missense variants in nearby residues (R4893W/Q/P, A4894P/T/V, G4897V) have been reported in the Human Gene Mutation Database in association with RYR1-related disorders (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.

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