Submissions for variant NM_000159.4(GCDH):c.1210G>A (p.Ala404Thr)

gnomAD frequency: 0.00005  dbSNP: rs201509112

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000388286	SCV000410871	uncertain significance	Glutaric aciduria, type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001553518	SCV001774402	uncertain significance	not provided	2020-10-01	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Fulgent Genetics, Fulgent Genetics	RCV000388286	SCV002815887	uncertain significance	Glutaric aciduria, type 1	2021-10-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000388286	SCV003270587	uncertain significance	Glutaric aciduria, type 1	2022-07-12	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 404 of the GCDH protein (p.Ala404Thr). This variant is present in population databases (rs201509112, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with GCDH-related conditions. ClinVar contains an entry for this variant (Variation ID: 328333). 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 GCDH 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.
GeneDx	RCV000413394	SCV000492199	uncertain significance	not specified	2016-11-23	flagged submission	clinical testing	The A404T missense variant in the GCDH gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A404T variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The 1000 Genomes Project Consortium reports A404T was observed in 3/206 alleles from individuals of Gujarati Indian background. The A404T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (V400M, R402W, R402Q, M405V) have been reported in the Human Gene Mutation Database in association with glutaric aciduria type I (GA1) (Stenson et al., 2014). In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Natera, Inc.	RCV000388286	SCV001460072	uncertain significance	Glutaric aciduria, type 1	2020-01-10	no assertion criteria provided	clinical testing