ClinVar Miner

Submissions for variant NM_001182.5(ALDH7A1):c.8G>T (p.Arg3Leu) (rs759866910)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186752 SCV000240319 uncertain significance not provided 2015-09-21 criteria provided, single submitter clinical testing p.Arg3Leu (CGC>CTC): c.8 G>T in exon 1 of the ALDH7A1 gene (NM_001182.3). The Arg3Leu missense change 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 2,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Arg3Leu is a non-conservative amino acid substitution as a positively charged Arginine residue is replaced with an uncharged Leucine residue. The variant occurs at a position in the protein that is conserved in most mammals. In silico algorithms are inconsistent in their predictions of pathogenicity for this missense change. Therefore, based on the currently available information, it is unclear whether Arg3Leu is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000702978 SCV000831856 uncertain significance Pyridoxine-dependent epilepsy 2018-05-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 3 of the ALDH7A1 protein (p.Arg3Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ALDH7A1-related disease. ClinVar contains an entry for this variant (Variation ID: 204854). 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 and their clinical significance is uncertain. 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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