ClinVar Miner

Submissions for variant NM_001099922.3(ALG13):c.2403G>C (p.Glu801Asp) (rs778396216)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000469041 SCV000541276 uncertain significance Epileptic encephalopathy, early infantile, 36 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 801 of the ALG13 protein (p.Glu801Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs778396216, ExAC 0.03%) but has not been reported in the literature in individuals with a ALG13-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000482857 SCV000572696 uncertain significance not specified 2017-02-03 criteria provided, single submitter clinical testing The E801D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E801D variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E801D variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Glutamic Acid are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

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