Submissions for variant NM_001080.3(ALDH5A1):c.1226G>A (p.Gly409Asp)

gnomAD frequency: 0.00001  dbSNP: rs118203984

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000001424	SCV000236519	pathogenic	Succinate-semialdehyde dehydrogenase deficiency	2014-08-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000001424	SCV000893708	pathogenic	Succinate-semialdehyde dehydrogenase deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000001424	SCV000945689	pathogenic	Succinate-semialdehyde dehydrogenase deficiency	2023-05-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ALDH5A1 function (PMID: 14635103, 28664505). 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 ALDH5A1 protein function. ClinVar contains an entry for this variant (Variation ID: 1359). This missense change has been observed in individual(s) with ALDH5A1-related disease (PMID: 14635103, 28664505). This variant is present in population databases (rs118203984, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 409 of the ALDH5A1 protein (p.Gly409Asp).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000001424	SCV001370109	pathogenic	Succinate-semialdehyde dehydrogenase deficiency	2018-10-05	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM3,PM2,PP3,PP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001424	SCV001554624	pathogenic	Succinate-semialdehyde dehydrogenase deficiency	2021-03-26	criteria provided, single submitter	clinical testing	Variant summary: ALDH5A1 c.1226G>A (p.Gly409Asp) 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 2.8e-05 in 251424 control chromosomes. c.1226G>A has been reported in the literature as homozygous or compound heterozygous with another pathogenic variant in multiple individuals affected with Succinic Semialdehyde Dehydrogenase Deficiency (e.g. Hogema_2001, Akaboshi_2003, Knerr_2010, Leo_2017). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <1% of normal SSADH activity (e.g. Hogema_2001, Akaboshi_2003). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001725927	SCV001961935	pathogenic	not provided	2021-08-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001725927	SCV002499791	pathogenic	not provided	2022-12-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that this variant was reported to have SSADH enzyme activity of less than 1% relative to wild-type (Akaboshi et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30829465, 11243727, 20304328, 28664505, 14635103, 32395407, 33531951, 32093054, 32402538, 33203024, 32887777)
3billion	RCV000001424	SCV002573356	pathogenic	Succinate-semialdehyde dehydrogenase deficiency	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 14635103). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.87). The variant has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001359). It has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 14635103 , 28664505). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Elsea Laboratory, Baylor College of Medicine	RCV000001424	SCV002820022	pathogenic	Succinate-semialdehyde dehydrogenase deficiency	2021-03-08	criteria provided, single submitter	curation
Lifecell International Pvt. Ltd	RCV000001424	SCV003842258	likely pathogenic	Succinate-semialdehyde dehydrogenase deficiency		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.1226G>A in Exon 8 of the ALDH5A1 gene that results in the amino acid substitution p.Gly409Asp was identified. The observed variant has a minor allele frequency of 0.00003 in gnomAD exomes and is novel in genomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID : 1359]. The observed variation has previously been reported for Succinic Semialdehyde Dehydrogenase Deficiency by Brennenstuhl, Heiko, et al., 2020. For these reasons this variant has been classified as Likely Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000001424	SCV004013924	pathogenic	Succinate-semialdehyde dehydrogenase deficiency	2023-05-23	criteria provided, single submitter	clinical testing	PS3, PM2, PP3, PP5
OMIM	RCV000001424	SCV000021574	pathogenic	Succinate-semialdehyde dehydrogenase deficiency	2003-12-01	no assertion criteria provided	literature only