Submissions for variant NM_001080.3(ALDH5A1):c.1316C>T (p.Thr439Ile)

gnomAD frequency: 0.00015  dbSNP: rs139633130

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000422683	SCV000512010	uncertain significance	not provided	2023-07-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000709920	SCV000946153	uncertain significance	Succinate-semialdehyde dehydrogenase deficiency	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 439 of the ALDH5A1 protein (p.Thr439Ile). This variant is present in population databases (rs139633130, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of succinic semialdehyde dehydrogenase (Invitae). ClinVar contains an entry for this variant (Variation ID: 377460). 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 with a negative predictive value of 80%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282138	SCV002572123	uncertain significance	not specified	2022-08-18	criteria provided, single submitter	clinical testing	Variant summary: ALDH5A1 c.1316C>T (p.Thr439Ile) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251344 control chromosomes (gnomAD), predominantly at a frequency of 0.00074 within the African or African-American subpopulation in the gnomAD database. To our knowledge, no occurrence of c.1316C>T in individuals affected with Succinic Semialdehyde Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported in the literature. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GenomeConnect, ClinGen	RCV000709920	SCV000840262	not provided	Succinate-semialdehyde dehydrogenase deficiency		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.