rs537038850
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_004453.4(ETFDH):c.79C>T(p.Pro27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000237 in 1,601,974 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004453.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152070Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251220Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135786
GnomAD4 exome AF: 0.0000248 AC: 36AN: 1449904Hom.: 0 Cov.: 26 AF XY: 0.0000235 AC XY: 17AN XY: 722038
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152070Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74276
ClinVar
Submissions by phenotype
Multiple acyl-CoA dehydrogenase deficiency Pathogenic:3Uncertain:1
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. -
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; internal data). 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
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not provided Pathogenic:1Uncertain:1
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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; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32007756, 32778825, 20023066, 27038534, 31268564) -
Glutaric acidemia type 2C Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at