rs754938068
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5
The NM_000016.6(ACADM):c.158G>A(p.Arg53His) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,461,722 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R53C) has been classified as Pathogenic.
Frequency
Consequence
NM_000016.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACADM | NM_000016.6 | c.158G>A | p.Arg53His | missense_variant | 3/12 | ENST00000370841.9 | NP_000007.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACADM | ENST00000370841.9 | c.158G>A | p.Arg53His | missense_variant | 3/12 | 1 | NM_000016.6 | ENSP00000359878.5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251346Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135882
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461722Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727166
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:3Uncertain:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 02, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 20, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 04, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 53 of the ACADM protein (p.Arg53His). This variant is present in population databases (rs754938068, gnomAD 0.01%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 22630369, 31033143; Invitae). ClinVar contains an entry for this variant (Variation ID: 226066). 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 ACADM protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACADM function (PMID: 26947917). This variant disrupts the p.Arg53 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8102510, 15832312, 16737882, 20434380, 22796001, 24623196). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 22, 2023 | Variant summary: ACADM c.158G>A (p.Arg53His) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251346 control chromosomes (gnomAD). c.158G>A has been reported in the literature in individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (examples: Touw_2012, Li_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant affecting the same residue (p.Arg53Cys) has been classified pathogenic in ClinVar (CV ID 92258). The following publications have been ascertained in the context of this evaluation (PMID: 31012112, 31033143, 22630369). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2021 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31012112, 22630369, 31033143, 33841490) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at