ClinVar Miner

Submissions for variant NM_001182.5(ALDH7A1):c.1559C>T (p.Ser520Phe)

dbSNP: rs1554097854
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000544167 SCV000640314 pathogenic Pyridoxine-dependent epilepsy 2024-10-03 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 520 of the ALDH7A1 protein (p.Ser520Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pyridoxine-responsive seizures (internal data). ClinVar contains an entry for this variant (Variation ID: 465325). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ALDH7A1 protein function with a positive predictive value of 95%. This variant disrupts the p.Ser520 amino acid residue in ALDH7A1. Other variant(s) that disrupt this residue have been observed in individuals with ALDH7A1-related conditions (PMID: 23350806), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002404449 SCV002705608 uncertain significance Inborn genetic diseases 2019-03-26 criteria provided, single submitter clinical testing The p.S520F variant (also known as c.1559C>T), located in coding exon 17 of the ALDH7A1 gene, results from a C to T substitution at nucleotide position 1559. The serine at codon 520 is replaced by phenylalanine, an amino acid with highly dissimilar properties. Another variant at the same position (reported as p.S492P) was reported in the homozygous state in an individual with ALDH7A1 deficiency (Pérez B et al. Epilepsia, 2013 Feb;54:239-48). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV003441932 SCV004168170 uncertain significance not provided 2023-10-03 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37580162)

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