Submissions for variant NM_000016.6(ACADM):c.683C>A (p.Thr228Asn)

dbSNP: rs149678400

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185662	SCV000238580	uncertain significance	not provided	2024-01-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(T203N); This variant is associated with the following publications: (PMID: 20434380, 26764160, 32778825, 23842438, 35629059, 31836396, 15171998, 18450854, 35281663, 23798014)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000211555	SCV000268480	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2015-02-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000211555	SCV000754910	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 228 of the ACADM protein (p.Thr228Asn). This variant is present in population databases (rs149678400, gnomAD 0.2%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 23842438; Invitae; 15171998 20434380). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203538). 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%. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000185662	SCV001715539	uncertain significance	not provided	2020-02-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000211555	SCV001786620	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2020-11-20	criteria provided, single submitter	clinical testing	The ACADM c.683C>A (p.Thr228Asn) variant is a missense variant which has been reported in four studies in a compound heterozygous state in six individuals with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (Hsu et al. 2008; Smith et al. 2010; Couce et al. 2013; Anderson et al. 2020). The p.Thr228Asn variant was also identified in another affected infant with a second variant, but the phase was not determined (McKinney et al. 2004). These individuals showed variable biochemical results including elevated acylglycines, serum medium chain acylcarnitines, C8-carnitine, C8/C10, and C8/C2 levels. However, some of biochemical parameters were within normal range in these individuals and it is suggested that this variant confers an attenuated effect (Smith et al. 2010; Couce et al. 2013; Anderson et al. 2020). The p.Thr228Asn variant is reported at a frequency of 0.001580 in the Latino/Admixed American population of the Genome Aggregation Database in a region of good sequence coverage. Based on collective evidence, the p.Thr228Asn variant is classified as likely pathogenic for medium-chain acyl-CoA dehydrogenase deficiency.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211555	SCV002500772	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-03-01	criteria provided, single submitter	clinical testing	Variant summary: ACADM c.683C>A (p.Thr228Asn) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251280 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (0.00029 vs 0.0054), allowing no conclusion about variant significance. c.683C>A has been reported in the literature in settings of newborn screening (NBS) in compound heterozygosity with other variants in this gene including multiple individuals with a pathogenic second variant in trans (example, McKinney_2004, Smith_2010, Couce_2013, Navarrete_2019, Anderson_2020, Alcaide_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20434380, 15171998, 23842438, 31836396, 30626930, 35629059). ClinVar contains an entry for this variant (Variation ID: 203538). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003398918	SCV004103893	likely pathogenic	ACADM-related disorder	2023-06-30	criteria provided, single submitter	clinical testing	The ACADM c.683C>A variant is predicted to result in the amino acid substitution p.Thr228Asn. This variant has been reported in the compound heterozygous state in over twelve individuals with biochemical medium chain acyl CoA dehydrogenase deficiency (Table 4 in McKinney et al 2004. PubMed ID: 15171998; Table 2 in Smith EH et al 2010. PubMed ID: 20434380; Couce ML et al 2013. PubMed ID: 23842438; Navarrete R et al 2019. PubMed ID: 30626930; Alcaide P. et al. 2022. PubMed ID: 35629059). In some patients this variant is predicted to mildly raise c8-carnitine levels and therefore many patients are only mildly affected or may be clinically asymptomatic (Anderson DR et al 2019. PubMed ID: 31836396; Alcaide P. et al. 2022. PubMed ID: 35629059). Lymphocytes from a patient with the c.683C>A variant in combination with a null variant exhibited 31% enzyme activity (Alcaide P. et al. 2022. PubMed ID: 35629059). This variant is reported in 0.16% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-76211574-C-A). In summary, we interpret this variant as likely pathogenic.
Baylor Genetics	RCV000211555	SCV004213907	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-03-28	criteria provided, single submitter	clinical testing