Submissions for variant NM_004453.4(ETFDH):c.79C>T (p.Pro27Ser)

gnomAD frequency: 0.00001  dbSNP: rs537038850

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153200	SCV000202674	uncertain significance	not provided	2014-02-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000392257	SCV000448152	uncertain significance	Multiple acyl-CoA dehydrogenase deficiency	2017-04-27	criteria provided, single submitter	clinical testing	The ETFDH c.79C>T (p.Pro27Ser) missense variant has been reported in a homozygous state in two siblings with late-onset (type III) multiple acyl-CoA dehydrogenase deficiency (MADD) and in a compound heterozygous state in one individual also with late-onset MADD (Pollard et al. 2010; Behim et al. 2016). Control data are unavailable for this variant. It is reported at a frequency of 0.00009 in the Latino population of the Exome Aggregation Consortium but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. The evidence for this variant is limited. The p.Pro27Ser variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for multiple acyl-CoA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000392257	SCV001421369	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 27 of the ETFDH protein (p.Pro27Ser). This variant is present in population databases (rs537038850, gnomAD 0.003%). This missense change has been observed in individual(s) with multiple Acyl-CoA dehydrogenase deficiency (PMID: 20023066, 27038534, 31268564; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 167040). 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 not expected to disrupt ETFDH protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ETFDH function (PMID: 31268564). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000153200	SCV001988920	pathogenic	not provided	2023-06-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 32007756, 32778825, 31268564, 20023066, 27038534)
Baylor Genetics	RCV000392257	SCV004194764	likely pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2023-10-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001831952	SCV002084834	likely pathogenic	Glutaric acidemia type 2C	2020-03-02	no assertion criteria provided	clinical testing