rs121434274
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000016.6(ACADM):βc.799G>Aβ(p.Gly267Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.00012 ( 0 hom., cov: 33)
Exomes π: 0.00022 ( 0 hom. )
Consequence
ACADM
NM_000016.6 missense
NM_000016.6 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 9.76
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.972
PP5
Variant 1-75749509-G-A is Pathogenic according to our data. Variant chr1-75749509-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749509-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ACADM | NM_000016.6 | c.799G>A | p.Gly267Arg | missense_variant | 9/12 | ENST00000370841.9 | NP_000007.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ACADM | ENST00000370841.9 | c.799G>A | p.Gly267Arg | missense_variant | 9/12 | 1 | NM_000016.6 | ENSP00000359878 | P4 |
Frequencies
GnomAD3 genomes 0.000118 AC: 18AN: 152110Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000215 AC: 54AN: 251384Hom.: 0 AF XY: 0.000228 AC XY: 31AN XY: 135896
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GnomAD4 exome AF: 0.000219 AC: 320AN: 1461790Hom.: 0 Cov.: 31 AF XY: 0.000227 AC XY: 165AN XY: 727200
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GnomAD4 genome 0.000118 AC: 18AN: 152110Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7AN XY: 74312
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:22
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:16
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 22, 2016 | Variant summary: The ACADM c.799G>A (p.Gly267Arg) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant, which was confirmed by at least one functional study (Sturm_2012). This variant was found in 26/121212 control chromosomes at a frequency of 0.0002145, which does not exceed the estimated maximal expected allele frequency of a pathogenic ACADM variant (0.0054233). The variant has been reported in numerous affected individuals in the literature in both the homozygous and compound heterozygous state (Andresen_2012, Sturm_2012, Gramer_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 08, 2020 | The ACADM c.799G>A; p.Gly267Arg variant (rs121434274) is reported in the literature in the compound heterozygous or homozygous state in several individuals affected with medium-chain acyl-CoA dehydrogenase deficiency (Andresen 1997, Koster 2014, Maier 2005, Sturm 2012, Yokota 1991, Zschocke 2001). This variant is reported in ClinVar (Variation ID: 3588), and is found in the general population with an overall allele frequency of 0.020% (57/282726 alleles) in the Genome Aggregation Database. The glycine at codon 267 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show a significant reduction in enzymatic activity (Andresen 1997, Zschocke 2001). Based on available information, this variant is considered to be pathogenic. References: Andresen BS et al. The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype? Hum Mol Genet. 1997 May;6(5):695-707. Koster KL et al. Functional studies of 18 heterologously expressed medium-chain acyl-CoA dehydrogenase (MCAD) variants. J Inherit Metab Dis. 2014 Nov;37(6):917-28. Maier EM et al. Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency. Hum Mutat. 2005 May;25(5):443-52. Sturm M et al. Functional effects of different medium-chain acyl-CoA dehydrogenase genotypes and identification of asymptomatic variants. PLoS One. 2012;7(9):e45110. Yokota I et al. Molecular survey of a prevalent mutation, 985A-to-G transition, and identification of five infrequent mutations in the medium-chain Acyl-CoA dehydrogenase (MCAD) gene in 55 patients with MCAD deficiency. Am J Hum Genet. 1991 Dec;49(6):1280-91. Zschocke J et al. Molecular and functional characterisation of mild MCAD deficiency. Hum Genet. 2001 May;108(5):404-8. - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID:1684086, 23028790, 16291504, 1684086, 22848008, 24966162, PM3_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24966162, 9158144, PS3_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000202, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.983, 3CNET: 0.998, PP3_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 03, 2020 | NM_000016.4(ACADM):c.799G>A(G267R) is classified as pathogenic in the context of medium chain acyl-CoA dehydrogenase deficiency. Sources cited for classification include the following: PMID: 20036593, 20434380, 23798014, 1684086, 24966162, 9158144 and 22542437. Classification of NM_000016.4(ACADM):c.799G>A(G267R) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.Γ’β¬Ε‘ΓβΓΒΆΓ’ΛΕ‘ΓβΓ’ΛΕ‘ΓΒ£ - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 30, 2022 | The p.Gly271Arg (NM_001127328.1 c.811G>A) variant in ACADM (also reported as NM_000016.4:p.Gly267Arg in the literature) has been reported in at least 4 homozygous and 5 compound heterozygous individuals with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency (Yokota 1991 PMID 1684086, Zschocke 2001 PMID: 11409868, Sturm 2012 PMID 23028790, Koster 2014 PMID 24966162). This variant has also been reported in ClinVar (Variation ID#3588) as pathogenic by multiple laboratories. It has been identified in 34/126698 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121434274), though this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies suggest that the p.Gly271Arg variant leads to reduced activity (Zschocke 2001 PMID: 11409868, Sturm 2012 PMID 23028790, Koster 2014 PMID 24966162). In summary, the p.Gly271Arg variant is pathogenic for MCAD deficiency in an autosomal recessive manner based upon observations in affected individuals and functional studies. ACMG/AMP Criteria applied: PS3, PM3,PP3,PP5. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 14, 2018 | The ACADM c.799G>A (p.Gly267Arg) missense variant has been reported in several studies in association with MCAD deficiency. Across a selection of available literature, the p.Gly267Arg variant has been found in at least 12 individuals affected with MCAD deficiency, in at least six in a compound heterozygous state, and in at least six in a homozygous state (Yokota et al. 1991; Zschocke et al. 2001; Maier et al. 2005; Sturm et al. 2012; Anderson et al. 2012). In general, the individuals who were homozygous for the variant were asymptomatic or presented with a mild phenotype, while individuals who were compound heterozygous for the variant displayed a moderate to severe phenotype (Maier et al. 2005; Sturm et al. 2012; Anderson et al. 2012). The p.Gly267Arg variant was found in two unaffected parents in a heterozygous state (Zschocke et al. 2001) and was absent from at least 12 controls. The p.Gly267Arg variant is reported at a frequency of 0.000487 in the South Asian population of the Genome Aggregation Database. The Gly267 residue is conserved. Expression studies of the p.Gly267Arg variant in E. coli revealed considerable residual MCAD activity of the protein (40%) compared to wild type (Andresen et al. 1997). In vitro activity of the p.Gly267Arg protein was markedly increased when co-expressed with GroESL chaperonins, indicating that the variant affects protein folding (Andresen et al. 1997). Another set of studies in E. coli showed that the p.Gly267Arg variant had low activity of <5% and was expressed at very low levels. This residue is predicted to be localized in a domain of beta-sheets involved in Flavin adenine nucleotide (FAD) binding (Koster et al. 2014). Based on the collective evidence, the p.Gly267Arg variant is classified as pathogenic for MCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 267 of the ACADM protein (p.Gly267Arg). This variant is present in population databases (rs121434274, gnomAD 0.05%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 1684086, 16291504, 22848008, 23028790; Invitae). ClinVar contains an entry for this variant (Variation ID: 3588). 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%. Experimental studies have shown that this missense change affects ACADM function (PMID: 9158144, 24966162). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1991 | - - |
| Pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | The ACADM c.799G>A (p.G267R) variant has been previously reported as pathogenic. The variant has been found in the homozygous or compound heterozygous state in individuals with medium-chain acyl-coA dehydrogenase deficiency (PMID: 1684086; 11409868; 23028790). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 26, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Apr 12, 2023 | ACMG categories: PS3,PM1,PM2,PP3,PP5 - |
| Pathogenic, no assertion criteria provided | clinical testing | Undiagnosed Diseases Network, NIH | Apr 30, 2020 | - - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Feb 23, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 02, 2020 | Expression studies demonstrate a reduced (13% to less than 10%) residual MCAD enzyme activity compared to wild-type and reduced protein expression on western blot analysis (Koster et al., 2014; Sturm et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23028790, 30609409, 31012112, 27760515, 20434380, 16291504, 25087612, 22975760, 24966162, 1684086, 9158144, 28492532, 23798014, 20036593, 25940036, 31589614, 32853555) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 23, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 24, 2018 | - - |
ACADM-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 27, 2023 | The ACADM c.799G>A variant is predicted to result in the amino acid substitution p.Gly267Arg. This variant, which has also been referred to in the literature as p.Gly242Arg, has been documented in the homozygous or compound heterozygous state in multiple medium chain acyl-CoA dehydrogenase deficiency (MCADD) patients (Yokota et al. 1991. PubMed ID: 1684086; Sturm et al. 2012. PubMed ID: 23028790; Koster et al. 2014. PubMed ID: 24966162). In functional studies, the MCAD protein levels and enzyme activity were significantly reduced (Sturm et al. 2012. PubMed ID: 23028790; Koster et al. 2014. PubMed ID: 24966162). In summary, we classify this variant as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
T;D;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;M;.;.
MutationTaster
Benign
A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;D;D;D
Vest4
MutPred
0.91
.;.;Gain of MoRF binding (P = 0.0144);.;
MVP
MPC
0.81
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at