ClinVar Miner

Submissions for variant NM_000126.4(ETFA):c.797C>T (p.Thr266Met) (rs119458970)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185868 SCV000238819 pathogenic not provided 2017-11-06 criteria provided, single submitter clinical testing The T266M missense pathogenic variant in the ETFA gene has been reported previously in association with glutaric aciduria II (GAII) and is the most frequent mutation identified in patients with ETF deficiency (Freneaux et al., 1992; Salazar et al., 1997). The variant is found in ETFA panel(s).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000185868 SCV000341276 pathogenic not provided 2016-04-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000332032 SCV000393968 pathogenic Multiple acyl-CoA dehydrogenase deficiency 2017-04-28 criteria provided, single submitter clinical testing The EFTA c.797C>T (p.Thr266Met) missense variant has been described in three studies in which it is found in a total of six patients with multiple acyl-CoA dehydrogenase deficiency, including in two in a homozygous state, in three in a compound heterozygous state, and in one in a heterozygous state (Freneaux et. al. 1992; Olsen et. al. 2003; Pontoizeau et al. 2015). The p.Thr266Met was absent from 54 controls and is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Thr266 residue is conserved. Functional studies demonstrated that the p.Thr266Met variant protein showed an altered flavin environment and reduced enzyme activity (Salazar et. al. 1997). Fatty acid oxidation assays in patient fibroblasts showed the variant resulted in a severely defective beta-oxidation flux, with 3% to 26% of oxidation compared to controls (Freneaux et al. 1992; Olsen et. al. 2003). Based on the evidence, the p.Thr266Met variant is classified as pathogenic for multiple acyl-CoA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000332032 SCV001227041 pathogenic Multiple acyl-CoA dehydrogenase deficiency 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 266 of the ETFA protein (p.Thr266Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs119458970, ExAC 0.01%). This variant has been observed in individual(s) with ETFA-related conditions (PMID: 1430199, 12815589, 16510302, 26409463). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2594). This variant has been reported to affect ETFA protein function (PMID: 9334218). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000002712 SCV000022870 pathogenic Glutaric acidemia IIA 2003-07-01 no assertion criteria provided literature only

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