ClinVar Miner

Submissions for variant NM_001182.5(ALDH7A1):c.364C>T (p.Arg122Trp) (rs370624118)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720683 SCV000851562 uncertain significance Seizures 2017-02-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000766382 SCV000240328 uncertain significance not provided 2016-06-01 criteria provided, single submitter clinical testing The R122W variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the 1000 Genomes Project. The R122W 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 in silico analysis predicts this variant is probably damaging to the protein structure/function. However, other missense mutations in nearby residues have not been reported in the Human Gene Mutation Database in association with ALDH7A1-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Genetic Services Laboratory, University of Chicago RCV000186761 SCV000593099 uncertain significance not specified 2015-09-28 criteria provided, single submitter clinical testing
Invitae RCV000556036 SCV000640323 uncertain significance Pyridoxine-dependent epilepsy 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 122 of the ALDH7A1 protein (p.Arg122Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs370624118, ExAC 0.03%). This variant has not been reported in the literature in individuals with ALDH7A1-related disease. ClinVar contains an entry for this variant (Variation ID: 204863). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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