Submissions for variant NM_001182.5(ALDH7A1):c.1004G>A (p.Arg335Gln)

gnomAD frequency: 0.00002  dbSNP: rs754449549

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186728	SCV000240295	pathogenic	not provided	2021-12-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on enzyme activity (Coulter-Mackie et al., 2012); This variant is associated with the following publications: (PMID: 19128417, 30043187, 32956737, 27342130, Ambegaonkar2017[abstract], 17068770, 24942048, 22784480)
Invitae	RCV000796632	SCV000936153	pathogenic	Pyridoxine-dependent epilepsy	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 335 of the ALDH7A1 protein (p.Arg335Gln). This variant is present in population databases (rs754449549, gnomAD 0.007%). This missense change has been observed in individual(s) with pyridoxine-dependent epilepsy (PMID: 17068770; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.920G>A (p.Arg307Gln). ClinVar contains an entry for this variant (Variation ID: 204832). 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 expected to disrupt ALDH7A1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ALDH7A1 function (PMID: 22784480). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000186728	SCV002497346	likely pathogenic	not provided	2022-01-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000796632	SCV004048968	likely pathogenic	Pyridoxine-dependent epilepsy	2023-04-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526634	SCV005039832	pathogenic	UDPglucose-4-epimerase deficiency	2024-03-18	criteria provided, single submitter	clinical testing	Variant summary: GALE c.1004G>A (p.Arg335His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250928 control chromosomes. c.1004G>A has been reported in the literature in individuals affected with UDPglucose-4-Epimerase Deficiency. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004539734	SCV005040770	pathogenic	Hereditary breast ovarian cancer syndrome	2024-03-18	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1004G>A (p.Arg335Gln) results in a conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 395984 control chromosomes (gnomAD). The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (2.1e-05), suggesting that the variant may be benign. c.1004G>A has been reported in the literature in individuals affected with breast cancer (e.g., Momozawa_2018, Uyisenga_2020) and at least one individual with ovarian cancer (e.g., Villy_2021) and one with colorectal cancer (e.g., Raskin_2017). These reports do not provide unequivocal conclusions about association of the variant with breast cancer. Co-occurrences with pathogenic variants have been observed in our lab (RAD51C c.706-2A>G and PMS2 c.2186_2187delTC, p.Leu729GlnfsX6), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12532420, 12414534, 29212164, 30287823, 32959997, 34541275). Nine submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS, n = 8, likely benign, n = 1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000796632	SCV005062067	pathogenic	Pyridoxine-dependent epilepsy	2024-03-18	criteria provided, single submitter	clinical testing	Variant summary: ALDH7A1 c.1004G>A (p.Arg335Gln) results in a conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR015590) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251132 control chromosomes (gnomAD). c.1004G>A has been reported in the literature in individuals affected with Pyridoxine-Dependent Epilepsy (e.g. Plecko_2007, Coughlin_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function and demonstrated an almost complete lack of activity for the variant protein (Coulter-Mackie_2012). The following publications have been ascertained in the context of this evaluation (PMID: 17068770, 30043187, 22784480). ClinVar contains an entry for this variant (Variation ID: 204832). Based on the evidence outlined above, the variant was classified as pathogenic.