ClinVar Miner

Submissions for variant NM_000159.4(GCDH):c.268G>A (p.Glu90Lys)

gnomAD frequency: 0.00004  dbSNP: rs1025558859
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000533495 SCV000631933 likely pathogenic Glutaric aciduria, type 1 2022-09-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 90 of the GCDH protein (p.Glu90Lys). This variant is present in population databases (no rsID available, gnomAD 0.008%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GCDH function (PMID: 28062662). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 459949). This missense change has been observed in individual(s) with glutaryl-CoA dehydrogenase deficiency (PMID: 10960496).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000533495 SCV002500344 likely pathogenic Glutaric aciduria, type 1 2022-03-02 criteria provided, single submitter clinical testing Variant summary: GCDH c.268G>A (p.Glu90Lys) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) 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 4e-06 in 251412 control chromosomes. c.268G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Glutaric aciduria, type 1 supported by characteristic biochemical elevations of both glutarate and 3-hydroxyglutarate (example, Busquets_2000). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in decreased GCDH protein stability in-vitro (example, Schmiesing_2017). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation further supported by modeling of protein sequence and biophysical properties performed at their laboratory. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV000533495 SCV004199245 likely pathogenic Glutaric aciduria, type 1 2023-05-09 criteria provided, single submitter clinical testing
Natera, Inc. RCV000533495 SCV002086958 likely pathogenic Glutaric aciduria, type 1 2021-09-27 no assertion criteria provided clinical testing

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