Submissions for variant NM_000016.6(ACADM):c.443G>A (p.Arg148Lys)

gnomAD frequency: 0.00003  dbSNP: rs778906552

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000179231	SCV000238578	pathogenic	not provided	2020-09-02	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22848008, 18241067, 20036593, 20434380, 27308838, 27477829, 23891399)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000211501	SCV000268496	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2021-05-08	criteria provided, single submitter	clinical testing	The ACADM c.443G>A; p.Arg148Lys variant (rs778906552) has been described in the compound heterozygous state and homozygously in individuals affected with medium chain acyl-CoA dehydrogenase (MCAD) deficiency (Anderson 2012, Arnold 2010, Smith 2010). It is reported as pathogenic in ClinVar (Variation ID: 198025) and observed in the Latino population at an overall frequency of 0.1% (35/35428 alleles) in the Genome Aggregation Database. In vitro fatty acid beta-oxidation analysis on fibroblasts from an individual homozygous for this variant was consistent with intermediate MCAD deficiency (Smith 2010). Based on available information, this variant is considered to be pathogenic. REFERENCES Anderson S et al. Medium chain acyl-CoA dehydrogenase deficiency detected among Hispanics by New Jersey newborn screening. Am J Med Genet A. 2012 Sep;158A(9):2100-5. 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. 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.
Eurofins Ntd Llc (ga)	RCV000179231	SCV000330907	pathogenic	not provided	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000211501	SCV000630286	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 148 of the ACADM protein (p.Arg148Lys). This variant is present in population databases (rs778906552, gnomAD 0.1%). This missense change has been observed in individual(s) with medium chain acyl-CoA dehydrogenase deficiency (PMID: 20036593, 20434380, 22848008). ClinVar contains an entry for this variant (Variation ID: 198025). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211501	SCV000693957	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2019-10-24	criteria provided, single submitter	clinical testing	Variant summary: ACADM c.443G>A (p.Arg148Lys) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain 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 0.00014 in 251320 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (0.00014 vs 0.0054), allowing no conclusion about variant significance. c.443G>A has been reported in the literature in multiple individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Anderson_2012, Smith_2010). These data indicate that the variant is very likely to be associated with disease. In vitro fatty acid beta-oxidation flux analysis of fibroblasts from one subject homozygous for the c.443G>A mutation demonstrated a phenotype consistent with intermediate MCAD deficiency (Smith_2010). Six ClinVar submissions (evaluation after 2014) cites the variant four times as pathogenic and twice as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800517	SCV000887493	likely pathogenic	not specified	2020-09-17	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Found in at least one patient with expected phenotype for this gene. Computational tools predict that this variant is damaging. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive.
Revvity Omics, Revvity	RCV000211501	SCV002023973	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2022-07-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000211501	SCV004212258	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-03-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000211501	SCV000486156	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2016-04-13	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000211501	SCV002092828	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2020-08-12	no assertion criteria provided	clinical testing