Submissions for variant NM_001182.5(ALDH7A1):c.529G>C (p.Ala177Pro)

gnomAD frequency: 0.00006  dbSNP: rs140102105

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255047	SCV000321395	likely pathogenic	not provided	2018-03-09	criteria provided, single submitter	clinical testing	A likely pathogenic variant has been identified in the ALDH7A1 gene. The A177P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. A different amino acid substitution at the same position (A177E, published as A149E) was reported in two patients with pyridoxine dependent epilepsy who had a second ALDH7A1 pathogenic variant on the other chromosome (Mills et al., 2010; Jain-Ghai et al., 2014). Additionally, A177P was observed with a pathogenic variant on the opposite allele (in trans) in a different patient referred for genetic testing at GeneDx. The A177P variant was not observed at a significant frequency in large population cohorts (Lek et al). The A177P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Revvity Omics, Revvity	RCV001785540	SCV002021342	likely pathogenic	Pyridoxine-dependent epilepsy	2019-11-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282091	SCV002570694	uncertain significance	not specified	2022-07-08	criteria provided, single submitter	clinical testing	Variant summary: ALDH7A1 c.529G>C (p.Ala177Pro) results in a non-conservative amino acid change located in the aldehyde dehydrogenase domain (IPR015590) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251398 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.529G>C has been reported in the literature in at least one compound heterozygous individual affected with Pyridoxine-Dependent Epilepsy (Coughlin_2019). These data do not allow any strong conclusion about the association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant at the same codon has been reported as pathogenic via ClinVar (p.Ala177Glu). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic variant.
Ambry Genetics	RCV002347969	SCV002643081	likely pathogenic	Inborn genetic diseases	2018-03-01	criteria provided, single submitter	clinical testing	The p.A177P variant (also known as c.529G>C), located in coding exon 6 of the ALDH7A1 gene, results from a G to C substitution at nucleotide position 529. The alanine at codon 177 is replaced by proline, an amino acid with highly similar properties. This alteration has been detected in trans with a mutation in an individual with pyridoxine-dependent epilepsy (Ambry internal data). Internal structural analysis indicates that this variant is structurally deleterious (Ambry internal data; Korasick DA et al. Chem. Biol. Interact., 2017 Oct;276:31-39; Brocker C et al. J. Biol. Chem., 2010 Jun;285:18452-63). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV001785540	SCV003471211	likely pathogenic	Pyridoxine-dependent epilepsy	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 177 of the ALDH7A1 protein (p.Ala177Pro). This variant is present in population databases (rs140102105, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of pyridoxine-dependent epilepsy (PMID: 30043187). ClinVar contains an entry for this variant (Variation ID: 265032). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALDH7A1 protein function. This variant disrupts the p.Ala177 amino acid residue in ALDH7A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20554659, 24664088, 24942048; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.