ClinVar Miner

Submissions for variant NM_000159.4(GCDH):c.877G>A (p.Ala293Thr) (rs121434371)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000790796 SCV000232914 pathogenic not provided 2014-01-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000002164 SCV000695723 pathogenic Glutaric aciduria, type 1 2017-05-26 criteria provided, single submitter clinical testing Variant summary: The GCDH c.877G>A (p.Ala293Thr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC and cohorts reported in the literature at a frequency of 0.0002717 (33/121474 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355). In the literature, the variant has been identified in numerous patients with glutaric acidemia type 1 in a homozygous and compound heterozygous state (van der Watt_MGM_2010; Christensen_JIMD_2004). Each of these studies also performed GCDH enzyme activity assays, which showed that the variant is a functional null allele, resulting in undetectable or very low activity (van der Watt_MGM_2010; Christensen_JIMD_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000002164 SCV000825501 pathogenic Glutaric aciduria, type 1 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 293 of the GCDH protein (p.Ala293Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs121434371, ExAC 0.06%). This variant has been observed to be homozygous or in combination with another GCDH variant in several individuals and families affected with glutaric aciduria type I (PMID: 8900227, 15573311, 10960496, 12199454, 8900228). ClinVar contains an entry for this variant (Variation ID: 2083). Experimental studies have shown that this missense change impairs GCDH enzyme activity in vitro (PMID: 8900227). For these reasons, this variant has been classified as Pathogenic.
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000002164 SCV000891512 uncertain significance Glutaric aciduria, type 1 2017-12-30 criteria provided, single submitter curation
Fulgent Genetics,Fulgent Genetics RCV000002164 SCV000893501 pathogenic Glutaric aciduria, type 1 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000002164 SCV000914831 pathogenic Glutaric aciduria, type 1 2018-10-23 criteria provided, single submitter clinical testing Across a selection of the available literature, the GCDH c.877G>A (p.Ala293Thr) variant has been identified in a homozygous state in 21 probands with glutaric acidemia and one asymptomatic individual, in a compound heterozygous state in 15 affected probands, and in a heterozygous state in 23 healthy individuals (Biery et al. 1996; Anikster et al. 1996; Busquets et al. 2000; Christensen et al. 2004; Van der Watt et al. 2010; Flamand-Rouviere et al. 2010). The p.Ala293Thr variant was absent from 50 controls but is reported at a frequency of 0.00058 in the African population of the Exome Aggregation Consortium. Functional studies performed in vivo using proband fibroblast or leukocyte cells demonstrated that the p.Ala293Thr variant resulted in zero to eleven percent of normal glutaryl-CoA dehydrogenase enzyme activity compared to controls, with homozygotes exhibiting less than one percent activity (Busquets et al. 2000; Christensen et al. 2004; Kolker et al. 2006; Flamand-Rouviere et al. 2010). Based on the collective evidence, the p.Ala293Thr variant is classified as pathogenic for glutaric acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Pathology and Clinical Laboratory Medicine,King Fahad Medical City RCV000002164 SCV000996291 pathogenic Glutaric aciduria, type 1 criteria provided, single submitter clinical testing
OMIM RCV000002164 SCV000022322 pathogenic Glutaric aciduria, type 1 1996-11-01 no assertion criteria provided literature only
Counsyl RCV000002164 SCV001132397 pathogenic Glutaric aciduria, type 1 2019-05-07 no assertion criteria provided clinical testing
GeneReviews RCV000002164 SCV001133280 pathogenic Glutaric aciduria, type 1 2019-09-12 no assertion criteria provided literature only Founder variant in South African Xhosa peoples
Natera, Inc. RCV000002164 SCV001456391 pathogenic Glutaric aciduria, type 1 2020-09-16 no assertion criteria provided clinical testing

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