ClinVar Miner

Submissions for variant NM_001182.5(ALDH7A1):c.1262C>T (p.Ala421Val)

gnomAD frequency: 0.00002  dbSNP: rs753598402
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186742 SCV000240309 uncertain significance not provided 2015-01-05 criteria provided, single submitter clinical testing p.Ala421Val (GCG>GTG): c.1262 C>T in exon 14 of the ALDH7A1 gene (NM_001182.4). The A421V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It 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 A421V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, 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. Additionally, missense mutations in nearby residues (P411L, T426P, E427Q, E427G, E427D and P431L) have been reported in association with pyridoxine-dependent epilepsy, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether the A421V variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV002517837 SCV003468871 uncertain significance Pyridoxine-dependent epilepsy 2022-08-04 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 421 of the ALDH7A1 protein (p.Ala421Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of ALDH7A1-related conditions (PMID: 30043187). ClinVar contains an entry for this variant (Variation ID: 204845). 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 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.
Genome-Nilou Lab RCV002517837 SCV004050602 uncertain significance Pyridoxine-dependent epilepsy 2023-04-11 criteria provided, single submitter clinical testing

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