ClinVar Miner

Submissions for variant NM_001182.5(ALDH7A1):c.1084C>T (p.Pro362Ser) (rs532800318)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186739 SCV000240306 uncertain significance not provided 2018-02-06 criteria provided, single submitter clinical testing The P362S variant has been previously reported in an individual with pyridoxine-dependent epilepsy (PDE) who was a compound heterozygote for 2 other ALDH7A1 variants; the P362S variant was found to be in cis with one of the pathogenic variants, and therefore, the authors suggested P362S was a rare benign variant (Nam et al., 2012). The P362S variant is observed in 19/18860 (0.1%) alleles from individuals of East Asian background, in large population cohorts (Lek et al., 2016). The P362S 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000690243 SCV000817924 uncertain significance Pyridoxine-dependent epilepsy 2018-04-10 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 362 of the ALDH7A1 protein (p.Pro362Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs532800318, ExAC 0.06%). This variant has not been reported in the literature in individuals with ALDH7A1-related disease. ClinVar contains an entry for this variant (Variation ID: 204842). 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: "Tolerated"; PolyPhen-2: "Possibly 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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