ClinVar Genomic variation as it relates to human health

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with succinic semialdehyde dehydrogenase deficiency (MIM#271980). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (13 heterozygotes, 0 homozygotes). (SP) 0402 - Variant is located in a gene associated with a severe early-onset recessive condition that is intolerant to biallelic loss of function variants (gnomAD). (SP) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity. NMD-predicted variants in this gene are well-reported as pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been previously reported in multiple individuals with succinic semialdehyde dehydrogenase deficiency (ClinVar, PMID: 11243727, 14635103, 26964512). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32238909, 32395407, 33393837, 32887777, 33679889, 25525159, 29431110, 11243727, 26964512, 14635103, 31589614)

The ALDH5A1 c.612G>A (p.Trp204Ter) variant is a stop-gained variant and is predicted to result in premature truncation of the protein. The p.Trp204Ter variant has been reported in three studies in which it is found in a total of ten individuals with succinic semialdehyde dehydrogenase (SSADH) deficiency, including in two who were homozygous for the variant, seven who carried the variant in a compound heterozygous state, and one who carried the variant in a heterozygous state where a second variant was not identified (Hogema et al. 2001; Akaboshi et al. 2003; Manrique Martin et al. 2018). The p.Trp204Ter variant was absent from 140 control chromosomes but is reported at a frequency of 0.000087 in the European (non-Finnish) population of the Genome Aggregation Database. During prenatal evaluation of one fetus carrying the variant in a compound heterozygous state, 4-hydroxybutyric acid levels in the amniotic fluid were increased and SSADH activity was decreased in amniocytes and chorionic villi (Hogema et al. 2001). Based on the evidence and the potential impact of stop-gained variants, the p.Trp204Ter variant is classified as pathogenic for succinic semialdehyde dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The p.Trp204X variant in ALDH5A1 has been identified in homozygous state in 2 in dividuals and in compound heterozygous state in 5 individuals with succinic semi aldehyde dehydrogenase deficiency. It has also been identified in 11/ 126714 Eur opean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broa dinstitute.org/; dbSNP rs118203982). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessiv e carrier frequency. This variant has been reported in ClinVar (Variation ID: 13 57). This nonsense variant leads to a premature termination codon at position 20 4, which is predicted to lead to a truncated or absent protein. Loss of function of the ALDH5A1 gene is an established disease mechanism in autosomal recessive succinic semialdehyde dehydrogenase deficiency. In summary, the p.Trp204X meets criteria to be classified as pathogenic for succinic semialdehyde dehydrogenase deficiency in an autosomal recessive manner. ACMG/AMP criteria applied: PVS1, PM 3_Strong, PM2_Supporting.

ACMG evidence PVS1, PM3, PP5

Variant summary: ALDH5A1 c.612G>A (p.Trp204X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory and in ClinVar. The variant allele was found at a frequency of 4.8e-05 in 251486 control chromosomes (gnomAD). c.612G>A has been reported in the literature in multiple bi-allelic individuals affected with Succinic Semialdehyde Dehydrogenase Deficiency (example: Akaboshi_2003). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 14635103). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Trp204*) in the ALDH5A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALDH5A1 are known to be pathogenic (PMID: 14635103). This variant is present in population databases (rs118203982, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with succinic semialdehyde dehydrogenase deficiency (PMID: 11243727, 14635103). ClinVar contains an entry for this variant (Variation ID: 1357). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.