ClinVar Miner

Submissions for variant NM_001182.5(ALDH7A1):c.1565G>C (p.Cys522Ser) (rs1057521316)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000431222 SCV000522186 uncertain significance not provided 2015-12-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALDH7A1 gene. The c.1565 G>C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant 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 c.1565 G>C variant is located immediately adjacent to the canonical donor site of intron 17 and several in-silico splice prediction models predict that his variant leads to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If c.1565 G>C does not alter splicing, it will result in the C522S missense change. The C522S 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 missense variants in nearby residues (R518G, R519K, S520P) have been reported in the Human Gene Mutation Database in association with pyridoxine-dependent epilepsy (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, 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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