Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000588049 | SCV000693958 | uncertain significance | not provided | 2017-03-12 | criteria provided, single submitter | clinical testing | Variant summary: The ACADM c.256G>A (p.Ala176Thr) variant involves the alteration of a highly conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. The Ala176 codon is located just outside of the MCAD conserved domain active site. The variant is absent from control datasets of ExAC and gnomAD (120956 chrs and 277152chrs tested, respectively). The variant is reported in at least 2 pts in trans with known a pathogenic mutation, c.985A>G, resulting elevated octanoylcarnitine (C8) levels. On the other hand, in compound heterozygosity with c.199T>C patients C8 level was similar to carrier profiles. One reputable database/clinical laboratory cite the variant as Pathogenic. Taking together, the variant of interest was classified as VUS-Possibly Pathogenic. |
| ARUP Laboratories, |
RCV001002215 | SCV001160089 | likely pathogenic | Medium-chain acyl-coenzyme A dehydrogenase deficiency | 2018-11-15 | criteria provided, single submitter | clinical testing | The ACADM c.526G>A; p.Ala176Thr variant, also known as Ala151Thr, has been described in the compound heterozygous state in individuals affected with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, presenting with elevated octanoylcarnitine (C8) levels (Arnold 2010, Nichols 2008, Smith 2010). It contains an entry in ClinVar (Variation ID: 495343), and is present on only 3 alleles in the Genome Aggregation Databases, indicating it is not a common polymorphism. The alanine at codon 176 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Based on available information, this variant is considered likely pathogenic. REFERENCES Arnold G et al. Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State. Mol Genet Metab. 2010 Mar;99(3):263-8. Nichols M et al. Novel mutations causing medium chain acyl-CoA dehydrogenase deficiency: under-representation of the common c.985 A > G mutation in the New York state population. Am J Med Genet A. 2008 Mar 1;146A(5):610-9. Smith E et al. Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing. Mol Genet Metab. 2010 Jul;100(3):241-50. |
| Gene |
RCV000588049 | SCV001821176 | uncertain significance | not provided | 2024-07-08 | criteria provided, single submitter | clinical testing | Described as a variant of uncertain significance and observed in the presence of a pathogenic variant in an individual with plasma and/or urine metabolites and biochemical studies similar to that of MCAD carriers (PMID: 20434380); Reported in individuals with a positive newborn screen for MCAD deficiency in whom a second variant was not described (PMID: 18241067, 20036593); Not observed at significant frequency in large population cohorts (gnomAD); 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: 20036593, 27477829, 18241067, 20434380) |
| Invitae | RCV001002215 | SCV002171276 | pathogenic | Medium-chain acyl-coenzyme A dehydrogenase deficiency | 2024-01-12 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 176 of the ACADM protein (p.Ala176Thr). This variant is present in population databases (no rsID available, gnomAD 0.008%). This missense change has been observed in individual(s) with ACADM-related conditions and/or medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 18241067, 20036593, 20434380; Invitae). ClinVar contains an entry for this variant (Variation ID: 495343). 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 with a positive predictive value of 80%. This variant disrupts the p.Ala176 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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. |
| Baylor Genetics | RCV001002215 | SCV004216296 | likely pathogenic | Medium-chain acyl-coenzyme A dehydrogenase deficiency | 2024-02-21 | criteria provided, single submitter | clinical testing |