chr1-75749507-A-G

Position:

chr1-75749507-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_000016.6(ACADM):c.797A>G(p.Asp266Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,613,994 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00016 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

ACADM
NM_000016.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.10

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-75749507-A-G is Pathogenic according to our data. Variant chr1-75749507-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75749507-A-G is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.36305082). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADM	NM_000016.6 linkuse as main transcript	c.797A>G	p.Asp266Gly	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 linkuse as main transcript	c.797A>G	p.Asp266Gly	missense_variant	9/12	1	NM_000016.6	ENSP00000359878	P4	P11310-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000318

AC:

AN:

251388

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000369

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.000152

AC:

222

AN:

1461816

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

108

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000161

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000158

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000300

Hom.:

Bravo

AF:

0.000155

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000436

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000830

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency

Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2022	Variant summary: ACADM c.797A>G (p.Asp266Gly) 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 0.00032 in 251388 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (0.00032 vs 0.0054), allowing no conclusion about variant significance. c.797A>G has been reported in the literature in compound heterozygous individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency, often with a milder level of enzyme deficiency reported (e.g. Maier_2005, Hsu_2008, Smith_2010, Andresen_2012, Anderson_2020, Tucci_2021). These data indicate that the variant is likely to be associated with disease. Experimental studies have found that the variant has 20-50% activity compared to the wild-type protein and is also less stable under thermal stress likely due to local protein unfolding (e.g. Maier_2009, Jank_2014). Ten submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and the majority have classified the variant as pathogenic (n=6) or likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 17, 2017	The ACADM c.797A>G, p.Asp266Gly (rs201375579), also known as D241G, has been reported in an individual with medium chain acyl-CoA dehydrogenase deficiency, in-trans with the common p.Lys329Glu pathogenic variant (Maier 2005). Functional characterization of the variant protein indicates reduced enzymatic activity and protein stability, likely due to the defects in monomer folding and tetramer formation (Jank 2014, Maier 2009). The variant is classified as pathogenic in ClinVar (Variation ID: 203540), and observed in the general population databases at a frequency of 0.08 percent in the Exome Variant Server (1/13006 alleles), and 0.03 percent in the Genome Aggregation Database (73/246234 alleles). Based on the above information, the variant is classified as pathogenic. References: Jank J et al. The domain-specific and temperature-dependent protein misfolding phenotype of variant medium-chain acyl-CoA dehydrogenase. PLoS One. 2014; 9(4):e93852. Maier E et al. Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency. Hum Mutat. 2005; 25(5):443-52. Maier E et al. Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screening. Hum Mol Genet. 2009; 18(9):1612-23. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 266 of the ACADM protein (p.Asp266Gly). This variant is present in population databases (rs201375579, gnomAD 0.06%). This missense change has been observed in individual(s) with medium chain acyl-CoA dehydrogenase (MCAD) deficiency (PMID: 19224950, 19780764, 22542437; Invitae). 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: 203540). 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%. Experimental studies have shown that this missense change affects ACADM function (PMID: 19224950, 24718418). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Dec 04, 2018	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 09, 2019	The variant has been reported along with a known ACADM pathogenic variant in newborns with medium chain acyl-CoA dehydrogenase (MCAD) deficiency in the published literature (PMIDs: 15832312 (2005), 19780764 (2009), 20434380 (2010), 22542437 (2012), and 27477829 (2016)). However, the biochemical effect of this variant on individuals varies and is not clear (PMID: 20434380 (2010)). Functional studies have reported that this variant results in enzyme misfolding and partial reduction of its activity (48% of wild type) (PMIDs: 19224950 (2009) and 24718418 (2014)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is disease causing or benign. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2024	Published functional studies demonstrate a damaging effect including reduced residual enzyme activity compared to wildtype and protein misfolding similar to the classic p.(K329E) pathogenic variant (PMID: 19224950, 24718418); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27477829, 31980526, 25087612, 24718418, 15832312, 22542437, 28492532, 20434380, 19780764, 32778825, 31589614, 33580884, 36840705, 19224950) -

Epileptic spasm

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

- -

ACADM-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2024

The ACADM c.797A>G variant is predicted to result in the amino acid substitution p.Asp266Gly. This variant has been reported in patients identified based on abnormal newborn screening results suggestive of medium chain acyl-CoA dehydrogenase deficiency (MCADD) (Maier et al. 2005. PubMed ID: 15832312; Andresen et al. 2012. PubMed ID: 22542437; Bentler et al. 2016. PubMed ID: 27477829). It is unclear whether the c.797A>G (p.Asp266Gly) variant is associated with a clinical phenotype (Smith et al. 2010. PubMed ID: 20434380). We have observed this variant at PreventionGenetics in the heterozygous state with a second pathogenic variant in several patients identified via newborn screening. In two functional studies, the p.Asp266Gly substitution was reported to have a severe effect on enzyme activity and protein stability, comparable to that observed from the known severe p.Lys329Glu substitution (Maier et al. 2009. PubMed ID: 19224950; Jank et al. 2014. PubMed ID: 24718418). In summary, we classify this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.094

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;D;T;.

Eigen

Benign

0.076

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.36

T;T;T;T

MetaSVM

Uncertain

0.57

MutationAssessor

Benign

0.46

.;N;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.1

D;D;D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.017

D;D;D;D

Sift4G

Uncertain

0.019

D;D;D;D

Polyphen

0.0010

B;B;B;B

Vest4

0.59

MVP

0.95

MPC

0.25

ClinPred

0.15

GERP RS

5.7

Varity_R

0.48

gMVP

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over