NM_004453.4:c.380T>A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_004453.4(ETFDH):c.380T>A(p.Leu127His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_004453.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ETFDH | NM_004453.4 | c.380T>A | p.Leu127His | missense_variant | Exon 3 of 13 | ENST00000511912.6 | NP_004444.2 | |
ETFDH | NM_001281737.2 | c.239T>A | p.Leu80His | missense_variant | Exon 2 of 12 | NP_001268666.1 | ||
ETFDH | NM_001281738.1 | c.197T>A | p.Leu66His | missense_variant | Exon 1 of 11 | NP_001268667.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251414Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135898
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461814Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727210
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Multiple acyl-CoA dehydrogenase deficiency Pathogenic:4
Variant summary: ETFDH c.380T>A (p.Leu127His) results in a non-conservative amino acid change in 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 8e-06 in 251414 control chromosomes (gnomAD). c.380T>A has been reported in the literature in multiple individuals affected with Glutaric Aciduria, Type 2c (example: Liang_2009, Wen_2010, Chien_2013, Lin_2019, Bylstra_2019 and Kuo_2021). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu127 amino acid residue in ETFDH. Other variant(s) that disrupt this residue have been observed in individuals with ETFDH-related conditions (PMID: 19249206, 19758981, 25119904), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 12030). This missense change has been observed in individual(s) with multiple acyl-CoA dehydrogenase deficiency (PMID: 19249206). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121964956, gnomAD 0.01%). This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 127 of the ETFDH protein (p.Leu127His). -
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Glutaric acidemia IIc Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at