Submissions for variant NM_001182.5(ALDH7A1):c.1468del (p.Ala490fs)

dbSNP: rs796052267

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186757	SCV000240324	pathogenic	not provided	2013-03-04	criteria provided, single submitter	clinical testing	The c.1468delG variant in the ALDH7A1 gene causes a frameshift starting with codon Alanine 490, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 28 of the new reading frame, denoted p.Ala490LeufsX28. This mutation is predicted to result in the replacement of the last 50 amino acids with 20 incorrect amino acids, leading to protein truncation. Although this pathogenic variant has not been previously reported to our knowledge, this result is consistent with a diagnosis of an ALDH7A1-related disorder. This variant has been observed to be apparently homozygous.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003225038	SCV003921930	pathogenic	Pyridoxine-dependent epilepsy	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with epilepsy, pyridoxine-dependent (MIM#266100). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other downstream protein-truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. At least four others have been reported in homozygous or compound heterozygous individuals with seizures (ClinVar, PMIDs: 30043187, 33748042). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. It has been reported in a homozygous individual with seizures (PMID: 29655203). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1005 - Clinically accredited laboratory assay specific to gene product shows abnormal protein function. Raised urinary piperideine-6-carboxylic was found in this individual. (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genome-Nilou Lab	RCV003225038	SCV004050095	pathogenic	Pyridoxine-dependent epilepsy	2023-04-11	criteria provided, single submitter	clinical testing