Submissions for variant NM_001182.5(ALDH7A1):c.1046G>C (p.Arg349Thr)

gnomAD frequency: 0.00001  dbSNP: rs553114356

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186738	SCV000240305	uncertain significance	not provided	2014-12-08	criteria provided, single submitter	clinical testing	p.Arg349Thr (AGA>ACA): c.1046 G>C in exon 12 of the ALDH7A1 gene (NM_001182.4). The R349T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is not conserved across species. However, the R349T variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In addition, a missense mutation in a nearby residue (Y354C) has been reported in association with pyridoxine-dependent epilepsy. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae	RCV000690729	SCV000818429	uncertain significance	Pyridoxine-dependent epilepsy	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 349 of the ALDH7A1 protein (p.Arg349Thr). This variant is present in population databases (rs553114356, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ALDH7A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 204841). 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 ALDH7A1 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.
Fulgent Genetics, Fulgent Genetics	RCV000690729	SCV000897183	uncertain significance	Pyridoxine-dependent epilepsy	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399694	SCV002710032	uncertain significance	Inborn genetic diseases	2019-09-23	criteria provided, single submitter	clinical testing	The p.R349T variant (also known as c.1046G>C), located in coding exon 12 of the ALDH7A1 gene, results from a G to C substitution at nucleotide position 1046. The arginine at codon 349 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000690729	SCV003823150	uncertain significance	Pyridoxine-dependent epilepsy	2023-09-27	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000690729	SCV004048924	uncertain significance	Pyridoxine-dependent epilepsy	2023-04-11	criteria provided, single submitter	clinical testing