Submissions for variant NM_001080.3(ALDH5A1):c.1348G>A (p.Asp450Asn)

gnomAD frequency: 0.00229  dbSNP: rs144177566

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000359989	SCV000340750	likely benign	not specified	2016-04-12	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000439066	SCV000511533	likely benign	not provided	2016-09-01	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
GeneDx	RCV000359989	SCV000622004	uncertain significance	not specified	2017-10-24	criteria provided, single submitter	clinical testing	The D450N variant in the ALDH5A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, D450N is reported as likely benign in ClinVar by different clinical laboratories, but additional evidence is not available (ClinVar SCV000340750.2; ClinVar SCV000511533.1; Landrum et al., 2016). This variant is observed in 177/24,038 alleles (0.74%) from individuals of African background in large population cohorts, including 2 homozygous control individuals (Lek et al., 2016). The D450N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret D450N as a variant of uncertain significance.
Invitae	RCV001086066	SCV000631987	benign	Succinate-semialdehyde dehydrogenase deficiency	2024-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001086066	SCV001319019	likely benign	Succinate-semialdehyde dehydrogenase deficiency	2018-01-13	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Genetic Services Laboratory, University of Chicago	RCV000359989	SCV002067679	uncertain significance	not specified	2018-12-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003909994	SCV004725845	benign	ALDH5A1-related condition	2022-06-21	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).