rs200724875
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000016.6(ACADM):c.617G>A(p.Arg206His) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,462 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R206L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000016.6 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 |
---|---|---|---|---|---|---|---|
ACADM | NM_000016.6 | c.617G>A | p.Arg206His | missense_variant | 8/12 | ENST00000370841.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADM | ENST00000370841.9 | c.617G>A | p.Arg206His | missense_variant | 8/12 | 1 | NM_000016.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152072Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251398Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135874
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461390Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9AN XY: 727038
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152072Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74252
ClinVar
Submissions by phenotype
Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg206 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10767181). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 ACADM protein function. ClinVar contains an entry for this variant (Variation ID: 92268). This missense change has been observed in individual(s) with biochemical profiles diagnostic for MCAD deficiency (PMID: 16291504, 20036593; Invitae). This variant is present in population databases (rs200724875, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 206 of the ACADM protein (p.Arg206His). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 15, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 07, 2024 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 09, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at