ClinVar Miner

Submissions for variant NM_000159.4(GCDH):c.572T>C (p.Met191Thr) (rs149120354)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724678 SCV000232017 likely pathogenic not provided 2015-04-20 criteria provided, single submitter clinical testing
Invitae RCV000179723 SCV000631938 pathogenic Glutaric aciduria, type 1 2020-08-02 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 191 of the GCDH protein (p.Met191Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs149120354, ExAC 0.02%). This variant has been reported as homozygous and in combination with another GCDH variant in individuals affected with glutaric aciduria type I (PMID: 9600243, 21031586, 28411331). ClinVar contains an entry for this variant (Variation ID: 198396). This variant has been observed in two individuals with GCDH enzymatic activity <0.5% of wild-type, findings that are highly specific for glutaric aciduria type I (PMID: 9600243). 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, but 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000179723 SCV000919424 pathogenic Glutaric aciduria, type 1 2018-04-16 criteria provided, single submitter clinical testing Variant summary: GCDH c.572T>C (p.Met191Thr) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase central domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-05 in 277158 control chromosomes. This frequency is not higher than expected for a pathogenic variant in GCDH causing Glutaric Acidemia Type 1, allowing no conclusion about variant significance. The c.572T>C has been reported in the literature in multiple individuals affected with Glutaric Acidemia Type 1. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000179723 SCV000677904 likely pathogenic Glutaric aciduria, type 1 2017-03-13 no assertion criteria provided clinical testing
Natera, Inc. RCV000179723 SCV001456388 pathogenic Glutaric aciduria, type 1 2020-09-16 no assertion criteria provided clinical testing

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