Submissions for variant NM_001182.5(ALDH7A1):c.328C>T (p.Arg110Ter)

gnomAD frequency: 0.00010  dbSNP: rs121912708

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415171	SCV000492931	pathogenic	Seizure; Ventriculomegaly	2015-01-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000480396	SCV000568347	pathogenic	not provided	2024-12-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect showing that the mutant enzyme had no detectable activity compared to wild type (PMID: 16491085); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18717709, 29875223, 30043187, 34645491, 31440721, 31019026, 25525159, 29286531, 31564432, 31623504, 31990480, 34426522, 34569664, 38250573, 16491085, 26232297, 26101365, 27342130)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000480396	SCV000610207	pathogenic	not provided	2017-06-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000019611	SCV000836492	pathogenic	Pyridoxine-dependent epilepsy	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg110*) 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). This variant is present in population databases (rs121912708, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with pyridoxine-dependent seizures (PMID: 16491085, 18717709, 26101365, 26232297). This variant is also known as c.244C>T, p.Arg82X. ClinVar contains an entry for this variant (Variation ID: 17995). For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000019611	SCV000996080	pathogenic	Pyridoxine-dependent epilepsy	2017-11-02	criteria provided, single submitter	clinical testing	The p.Arg119Ter variant (also referred to as p.Arg82Ter in the literature) is a stop-gained variant that is predicted to result in the premature truncation of the ALDH7A1 protein. This variant has been reported in two patients, once in the homozygous state and once in the compound heterozygous state that is identical to that seen in this patient (PMID: 16491085). This variant combination was shown to result in an absence of enzyme activity via in vitro functional expression studies in Chinese hamster ovary cells (PMID: 16491085). The highest reported allele frequency in the population database, gnomAD, is 0.0001 (13/126702 alleles). Based on the available evidence, the p.Arg119Ter variant is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000480396	SCV001335138	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	ALDH7A1: PM3:Very Strong, PVS1, PM2
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000019611	SCV001370467	pathogenic	Pyridoxine-dependent epilepsy	2019-11-05	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Revvity Omics, Revvity	RCV000019611	SCV002024849	pathogenic	Pyridoxine-dependent epilepsy	2020-11-17	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251913	SCV002523106	pathogenic	See cases	2021-03-25	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PS4, PM2, PM3
Ambry Genetics	RCV002444436	SCV002611668	pathogenic	Inborn genetic diseases	2022-03-28	criteria provided, single submitter	clinical testing	The c.328C>T (p.R110*) alteration, located in exon 4 (coding exon 4) of the ALDH7A1 gene, consists of a C to T substitution at nucleotide position 328. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 110. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.01% (18/282868) total alleles studied. The highest observed frequency was 0.01% (1/7222) of Other alleles. This alteration has been reported in the homozygous and compound heterozygous states in multiple individuals with pyridoxine-dependent epilepsy (Cirillo, 2015; Kingsmore, 2019; Mills, 2006; Tincheva, 2015). Based on the available evidence, this alteration is classified as pathogenic.
Genome-Nilou Lab	RCV000019611	SCV004050220	pathogenic	Pyridoxine-dependent epilepsy	2023-04-11	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000019611	SCV004801218	pathogenic	Pyridoxine-dependent epilepsy	2024-03-14	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000019611	SCV005399838	pathogenic	Pyridoxine-dependent epilepsy	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, 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, early-onset, 4, vitamin B6-dependent (MIM#266100). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (76 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants have been reported as pathogenic or likely pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported eleven times as pathogenic by clinical testing laboratories (ClinVar). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000019611	SCV000039909	pathogenic	Pyridoxine-dependent epilepsy	2006-03-01	no assertion criteria provided	literature only