1-75740037-G-A

Variant names:

• chr1-75740037-G-A
• rs200754053
• NM_000016.6:c.526G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000016.6(ACADM):​c.526G>A​(p.Ala176Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,774 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. A176S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 9.85
• Publications: 9 publications found

Genes affected

ACADM (HGNC:89): (acyl-CoA dehydrogenase medium chain) This gene encodes the medium-chain specific (C4 to C12 straight chain) acyl-Coenzyme A dehydrogenase. The homotetramer enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Defects in this gene cause medium-chain acyl-CoA dehydrogenase deficiency, a disease characterized by hepatic dysfunction, fasting hypoglycemia, and encephalopathy, which can result in infantile death. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACADM Gene-Disease associations (from GenCC):

• medium chain acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, ClinGen, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000016.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 95 curated pathogenic missense variants (we use a threshold of 10). The gene has 29 curated benign missense variants. Gene score misZ: 0.54287 (below the threshold of 3.09). Trascript score misZ: 0.41658 (below the threshold of 3.09). GenCC associations: The gene is linked to medium chain acyl-CoA dehydrogenase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 1-75740037-G-A is Pathogenic according to our data. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343. Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADM	NM_000016.6	c.526G>A	p.Ala176Thr	missense_variant	Exon 7 of 12	ENST00000370841.9	NP_000007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9	c.526G>A	p.Ala176Thr	missense_variant	Exon 7 of 12	1	NM_000016.6	ENSP00000359878.5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251382 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460606 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726696

African (AFR) AF: 0.000150 AC: 5 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111094

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152168 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74340

African (AFR) AF: 0.0000724 AC: 3 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:5

Jun 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Feb 21, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 11, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ACADM c.526G>A (p.Ala176Thr) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 8e-06 in 251382 control chromosomes. c.526G>A has been observed in individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Nichols_2008, Smith_2010, Arnold_2010, Internal data). These data indicate that the variant is 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: 18241067, 20434380, 20036593). ClinVar contains an entry for this variant (Variation ID: 495343). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Oct 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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; internal data). ClinVar contains an entry for this variant (Variation ID: 495343). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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 (internal data). 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. -

not provided Uncertain:1

May 19, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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; Also known as p.(A151T); This variant is associated with the following publications: (PMID: 20036593, 27477829, 18241067, 20434380) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;D;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.6	.;H;.;.
PhyloP100		9.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.95
MutPred		0.95		.;.;Gain of phosphorylation at A209 (P = 0.0739);.;
MVP		1.0
MPC		0.68
ClinPred		0.97	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.91
Mutation Taster		=168/132	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200754053; hg19: chr1-76205722;