Submissions for variant NM_001182.5(ALDH7A1):c.575C>T (p.Thr192Met)

gnomAD frequency: 0.00001  dbSNP: rs376917645

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255618	SCV000321396	pathogenic	not provided	2021-04-01	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in a patient with epilepsy and/or a neurodevelopmental disorder, but additional information was not provided (Lindy et al., 2018); This variant is associated with the following publications: (PMID: 32956737, 30043187, 29655203)
CeGaT Center for Human Genetics Tuebingen	RCV000255618	SCV000693185	uncertain significance	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691250	SCV000819002	pathogenic	Pyridoxine-dependent epilepsy	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 192 of the ALDH7A1 protein (p.Thr192Met). This variant is present in population databases (rs376917645, gnomAD 0.007%). This missense change has been observed in individual(s) with epilepsy (PMID: 29655203; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265033). 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%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000691250	SCV005039746	likely pathogenic	Pyridoxine-dependent epilepsy	2024-03-19	criteria provided, single submitter	clinical testing	Variant summary: ALDH7A1 c.575C>T (p.Thr192Met) 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 1.2e-05 in 251476 control chromosomes (gnomAD). c.575C>T has been reported in the literature in individuals affected with Pyridoxine-Dependent Epilepsy (Lindy_2018, Couglin_2019, GIbaud_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29655203, 30043187, 33748042). ClinVar contains an entry for this variant (Variation ID: 265033). Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003422188	SCV004118289	likely pathogenic	ALDH7A1-related disorder	2024-01-02	no assertion criteria provided	clinical testing	The ALDH7A1 c.575C>T variant is predicted to result in the amino acid substitution p.Thr192Met. This variant has been reported in multiple individuals with epilepsy and/or neurodevelopmental disorders (Lindy et al. 2018. PubMed ID: 29655203, table S4; Coughlin et al. 2019. PubMed ID: 30043187, Supp Table II). It was reported in the compound heterozygous state with a pathogenic variant in two individual in the literature (Coughlin CR 2nd et al. 2019. PubMed ID: 30043187, Supp Table II) and by a diagnostic lab in ClinVar, where it has classifications of uncertain and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/265033/). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Taken together, we classify this variant to be likely pathogenic.