Submissions for variant NM_001080.3(ALDH5A1):c.50C>T (p.Ser17Leu)

gnomAD frequency: 0.00021  dbSNP: rs753168976

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000331869	SCV000337200	uncertain significance	not provided	2015-11-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000401818	SCV000461806	uncertain significance	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, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000401818	SCV000632003	uncertain significance	Succinate-semialdehyde dehydrogenase deficiency	2022-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 17 of the ALDH5A1 protein (p.Ser17Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with intellectual disability, developmental delay and/or multiple congenital anomalies (PMID: 30091983). ClinVar contains an entry for this variant (Variation ID: 284542). 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 not expected to disrupt ALDH5A1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV000401818	SCV001521824	uncertain significance	Succinate-semialdehyde dehydrogenase deficiency	2019-03-07	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV000401818	SCV002798262	uncertain significance	Succinate-semialdehyde dehydrogenase deficiency	2022-01-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002518935	SCV003676690	uncertain significance	Inborn genetic diseases	2022-05-04	criteria provided, single submitter	clinical testing	The c.50C>T (p.S17L) alteration is located in exon 1 (coding exon 1) of the ALDH5A1 gene. This alteration results from a C to T substitution at nucleotide position 50, causing the serine (S) at amino acid position 17 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000331869	SCV005050257	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing