Submissions for variant NM_001182.5(ALDH7A1):c.664A>G (p.Thr222Ala)

gnomAD frequency: 0.00003  dbSNP: rs777829351

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186729	SCV000240296	pathogenic	not provided	2022-10-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 32956737, 30043187, 29286531)
Invitae	RCV000466667	SCV000551312	pathogenic	Pyridoxine-dependent epilepsy	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 222 of the ALDH7A1 protein (p.Thr222Ala). This variant is present in population databases (rs777829351, gnomAD 0.006%). This missense change has been observed in individual(s) with pyridoxine-dependent epilepsy (PMID: 29286531, 30043187; Invitae). ClinVar contains an entry for this variant (Variation ID: 204833). 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 80%. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000466667	SCV001318348	uncertain significance	Pyridoxine-dependent epilepsy	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000466667	SCV001369117	likely pathogenic	Pyridoxine-dependent epilepsy	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. This variant was detected in homozygous state.
Ambry Genetics	RCV002362975	SCV002662210	uncertain significance	Inborn genetic diseases	2017-09-25	criteria provided, single submitter	clinical testing	The p.T222A variant (also known as c.664A>G), located in coding exon 7 of the ALDH7A1 gene, results from an A to G substitution at nucleotide position 664. The threonine at codon 222 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000466667	SCV003844976	pathogenic	Pyridoxine-dependent epilepsy	2023-02-19	criteria provided, single submitter	clinical testing	Variant summary: ALDH7A1 c.664A>G (p.Thr222Ala) results in a non-conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR015590) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249894 control chromosomes (gnomAD). c.664A>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Pyridoxine-Dependent Epilepsy (e.g. Tumiene_2018, Coughlin_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, one as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.