Submissions for variant NM_001182.5(ALDH7A1):c.503_506del (p.Ile168fs)

gnomAD frequency: 0.00002  dbSNP: rs1064794241

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486613	SCV000568346	pathogenic	not provided	2017-02-08	criteria provided, single submitter	clinical testing	The c.503_506delTCTT pathogenic variant in the ALDH7A1 gene has been reported previously (using the alternative nomenclature of c.419_422delTCTT) in an individual with folinic-acid responsive seizures and elevated pipecolic acid in CSF who also had a second ALDH7A1 variant identified (Nicolai et al., 2006; Gallagher et al., 2009). The deletion causes a frameshift starting with codon Isoleucine 168, changes this amino acid to a Serine residue and creates a premature Stop codon at position 10 of the new reading frame, denoted p.Ile168SerfsX10. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.503_506delTCTT variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, the c.503_506delTCTT variant is considered a pathogenic variant.
Invitae	RCV001066514	SCV001231527	pathogenic	Pyridoxine-dependent epilepsy	2023-06-03	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 420018). This variant is also known as c.419_422delTCTT (p.Ile140Serfs*10). This premature translational stop signal has been observed in individual(s) with pyridoxine-dependent epilepsy (PMID: 19142996). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ile168Serfs*10) in the ALDH7A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALDH7A1 are known to be pathogenic (PMID: 16491085, 20554659). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001066514	SCV002024816	pathogenic	Pyridoxine-dependent epilepsy	2019-06-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001066514	SCV002548158	pathogenic	Pyridoxine-dependent epilepsy	2022-05-19	criteria provided, single submitter	clinical testing	Variant summary: ALDH7A1 c.503_506delTCTT (p.Ile168SerfsX10) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251422 control chromosomes. c.503_506delTCTT has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with Pyridoxine-Dependent Epilepsy (example, Gallagher_2009, Mills_2010) and continues to be subsequently cited by others (example, Coughlin_2019, Scharer_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV001066514	SCV004049794	pathogenic	Pyridoxine-dependent epilepsy	2023-04-11	criteria provided, single submitter	clinical testing