ClinVar Miner

Submissions for variant NM_001182.5(ALDH7A1):c.1513G>C (p.Gly505Arg)

gnomAD frequency: 0.00004  dbSNP: rs556400964
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186750 SCV000240317 pathogenic not provided 2023-03-21 criteria provided, single submitter clinical testing Published functional studies demonstrate this variant abolishes ATQ enzyme activity (Coulter-Mackie et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31440721, 22784480, 19128417, 22728861, 30043187, 31980526, 32685344, 31589614, 24613284, 23350806, 20814824)
Invitae RCV000545498 SCV000640311 pathogenic Pyridoxine-dependent epilepsy 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 505 of the ALDH7A1 protein (p.Gly505Arg). This variant is present in population databases (rs556400964, gnomAD 0.03%). This missense change has been observed in individual(s) with pyridoxine-dependent epilepsy (PMID: 19128417, 20554659, 20814824, 23350806, 24942048). This variant is also known as c.1429G>C, p.Gly477Arg. ClinVar contains an entry for this variant (Variation ID: 204852). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ALDH7A1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ALDH7A1 function (PMID: 22784480). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000545498 SCV000893681 pathogenic Pyridoxine-dependent epilepsy 2018-10-31 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000545498 SCV002024317 pathogenic Pyridoxine-dependent epilepsy 2023-03-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000545498 SCV002548157 pathogenic Pyridoxine-dependent epilepsy 2022-05-03 criteria provided, single submitter clinical testing Variant summary: ALDH7A1 c.1513G>C (p.Gly505Arg, also reported as p.Gly477Arg) results in a non-conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR015590) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 251310 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ALDH7A1 causing Pyridoxine-Dependent Epilepsy (8.8e-05 vs 0.0018), allowing no conclusion about variant significance. c.1513G>C has been reported in the literature in multiple compound heterozygous individuals affected with Pyridoxine-Dependent Epilepsy (e.g. Bennett_2009, Alfadhel_2012, Perez_2013, Kava_2020) and at least one homozygous individual (Perez_2013). These data indicate that the variant is very likely to be associated with disease. One publication using an E.coli expression system found that ALDH7A1 protein with the variant had less than 3% enzymatic activity (Coulter-Mackie_2012). Four ClinVar submitters have assessed the variant since 2014: all four classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab RCV000545498 SCV004050028 pathogenic Pyridoxine-dependent epilepsy 2023-04-11 criteria provided, single submitter clinical testing

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