ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.14416A>G (p.Asn4806Asp) (rs886039586)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255902 SCV000322471 pathogenic not provided 2016-07-26 criteria provided, single submitter clinical testing The N4806D pathogenic variant in the RYR1 gene has been reported previously in an individual with congenital myopathy who was compound heterozygous for the N4806D pathogenic variant and another likely pathogenic variant (Klein et al., 2012). Function studies have shown the N4806D variant results in impairment of the calcium release channel function and regulation (Du et al., 1998). The N4806D variant was not observed in approximately 6500 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 N4806D variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255902 SCV000331383 uncertain significance not provided 2015-10-19 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000255902 SCV000852410 likely pathogenic not provided 2015-08-07 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000784911 SCV000923452 uncertain significance not specified 2019-01-01 criteria provided, single submitter clinical testing
Invitae RCV001047738 SCV001211718 likely pathogenic RYR1-Related Disorders 2019-01-15 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 4806 of the RYR1 protein (p.Asn4806Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in the compound heterozygous state in several individuals affected with RYR1-related conditions (PMID: 22473935, 27234031, 28818389, 25960145). ClinVar contains an entry for this variant (Variation ID: 265505). 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"). 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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