rs121434274

chr1-75749509-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000016.6(ACADM):c.799G>A(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000016.6
• 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	UniProt
ACADM	NM_000016.6	c.799G>A	p.Gly267Arg	missense_variant	9/12	ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.799G>A	p.Gly267Arg	missense_variant	9/12	1	NM_000016.6	P4

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152110 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000215 AC: 54 AN: 251384 Hom.: 0 AF XY: 0.000228 AC XY: 31 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000219 AC: 320 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.000227 AC XY: 165 AN XY: 727200

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000452

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000231

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152110 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74312

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.000174

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:15

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, no assertion criteria provided	literature only	OMIM	Dec 01, 1991	- -
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	Revvity Omics, Revvity	Jun 26, 2023	- -
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.‚Äã -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 26, 2023	- -
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	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	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. -
Pathogenic, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	Apr 30, 2020	- -
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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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	clinical testing	Natera, Inc.	Mar 17, 2017	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 23, 2014	- -
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	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 23, 2016	- -
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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T;D;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.7	D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.96
MutPred		0.91		.;.;Gain of MoRF binding (P = 0.0144);.;
MVP		0.98
MPC		0.81
ClinPred		0.76	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434274; hg19: chr1-76215194;