rs746598421
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_004453.4(ETFDH):c.1414G>A(p.Gly472Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G472A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004453.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ETFDH | NM_004453.4 | c.1414G>A | p.Gly472Arg | missense_variant | 11/13 | ENST00000511912.6 | |
ETFDH | NM_001281737.2 | c.1273G>A | p.Gly425Arg | missense_variant | 10/12 | ||
ETFDH | NM_001281738.1 | c.1231G>A | p.Gly411Arg | missense_variant | 9/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ETFDH | ENST00000511912.6 | c.1414G>A | p.Gly472Arg | missense_variant | 11/13 | 1 | NM_004453.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251366Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135854
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461116Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18AN XY: 726882
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Multiple acyl-CoA dehydrogenase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 23, 2023 | - - |
Pathogenic, criteria provided, single submitter | curation | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Jun 12, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 26, 2022 | Variant summary: ETFDH c.1414G>A (p.Gly472Arg) 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 3.6e-05 in 251366 control chromosomes. c.1414G>A has been reported in the literature as a homozygous genotype in several individuals affected with Multiple acyl-CoA dehydrogenase deficiency (MADD) or glutaric aciduria type II (example, Olsen_2003, Ali_2021, van Rijt_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in homozygous individuals as measured by beta oxidation activity in whole fibroblast cells (Olsen_2003). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=2). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 472 of the ETFDH protein (p.Gly472Arg). This variant is present in population databases (rs746598421, gnomAD 0.03%). This missense change has been observed in individual(s) with multiple Acyl-CoA dehydrogenase deficiency (PMID: 12815589, 31268564; Invitae). ClinVar contains an entry for this variant (Variation ID: 459963). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ETFDH function (PMID: 12815589, 31268564). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Glutaric acidemia type 2C Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 23, 2021 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 27, 2023 | Published functional studies demonstrate p.(G472R) significantly reduced protein expression and activity (PMID: 22611163); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 34573316, 31268564, 12815589, 22611163) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at