ClinVar Miner

Submissions for variant NM_000159.4(GCDH):c.892G>A (p.Ala298Thr) (rs761765983)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494627 SCV000582339 pathogenic not provided 2016-03-19 criteria provided, single submitter clinical testing An individual with GA1 who is apparently homozygous for the A298T variant was found to have5-10% residual glutaryl-CoA dehydrogenase enzyme activity in fibroblasts (Christensen et al., 2004).The A298T variant has also been described in two compound heterozygous individuals withbiochemically confirmed GA1 (Tang et al., 2000; Lee et al., 2012). The A298T variant was notobserved in approximately 6500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these population. In summary, we interpret A298T to be a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587206 SCV000695724 pathogenic Glutaric aciduria, type 1 2017-04-26 criteria provided, single submitter clinical testing Variant summary: The GCDH c.892G>A (p.Ala298Thr) variant located in the Acyl-CoA dehydrogenase/oxidase C-terminal (via InterPro) involves the alteration of a non-conserved nucleotide and 2/4 in silico tools (SNPsandGO not captured here due to low reliability index) predict a benign outcome. This variant was found in 3/120372 control chromosomes at a frequency of 0.0000249, which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355). Multiple publications have cited the variant in affected homozygote and compound heterozygote individuals. Functional analysis found no enzyme activity for a homozygous affected individual and ~50% activity for a unaffected carrier. Therefore, the variant of interest has been classified as "pathogenic."
Invitae RCV000587206 SCV000955539 pathogenic Glutaric aciduria, type 1 2020-09-03 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 298 of the GCDH protein (p.Ala298Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs761765983, ExAC 0.01%). This variant has been observed in individuals affected with Glutaric acidemia type I (PMID: 11058907, 15505393, 23104440, 26656312, 27672653). ClinVar contains an entry for this variant (Variation ID: 429706). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000587206 SCV000789856 likely pathogenic Glutaric aciduria, type 1 2017-02-23 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.