ClinVar Miner

Submissions for variant NM_004453.4(ETFDH):c.1832G>A (p.Gly611Glu)

gnomAD frequency: 0.00002  dbSNP: rs761669036
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255489 SCV000321606 likely pathogenic not provided 2023-05-05 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20138856, 12359134, 32778825)
Invitae RCV001069003 SCV001234143 pathogenic Multiple acyl-CoA dehydrogenase deficiency 2023-09-08 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 611 of the ETFDH protein (p.Gly611Glu). This variant is present in population databases (rs761669036, gnomAD 0.02%). This missense change has been observed in individual(s) with glutaric acidemia type II (PMID: 12359134; Invitae). ClinVar contains an entry for this variant (Variation ID: 265124). 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 ETFDH protein function. This variant disrupts the p.Gly611 amino acid residue in ETFDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20138856). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001069003 SCV004194815 likely pathogenic Multiple acyl-CoA dehydrogenase deficiency 2023-07-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001069003 SCV004241808 pathogenic Multiple acyl-CoA dehydrogenase deficiency 2023-12-04 criteria provided, single submitter clinical testing Variant summary: ETFDH c.1832G>A (p.Gly611Glu) results in a non-conservative amino acid change located in the ETF-QO/FixX, C-terminal domain (IPR007859) 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 2.8e-05 in 251380 control chromosomes. c.1832G>A has been reported in the literature in multiple individuals affected with biochemically confirmed features of Glutaric Aciduria, Type 2c (example, Goodman_2002, Adhikari_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Additionally, a different missense variant affecting the same amino acid, c.1831G>A (p.Glu611Arg), has been reported in individuals affected with Glutaric Aciduria, Type 2 supporting the functional relevance of this residue to ETFDH function. The following publications have been ascertained in the context of this evaluation (PMID: 32778825, 12359134). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV001833298 SCV002084876 likely pathogenic Glutaric acidemia type 2C 2020-03-18 no assertion criteria provided clinical testing

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