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NM_000016.6(ACADM):c.797A>G (p.Asp266Gly)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(4);Pathogenic(4);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
11 (Most recent: Nov 19, 2021)
Last evaluated:
Oct 8, 2020
Accession:
VCV000203540.14
Variation ID:
203540
Description:
single nucleotide variant
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NM_000016.6(ACADM):c.797A>G (p.Asp266Gly)

Allele ID
199977
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
1p31.1
Genomic location
1: 75749507 (GRCh38) GRCh38 UCSC
1: 76215192 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000001.10:g.76215192A>G
LRG_838:g.30150A>G
LRG_838t1:c.797A>G LRG_838p1:p.Asp266Gly
... more HGVS
Protein change
D266G, D270G, D299G, D77G, D230G
Other names
p.D266G:GAC>GGC
Canonical SPDI
NC_000001.11:75749506:A:G
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00015
The Genome Aggregation Database (gnomAD), exomes 0.00032
The Genome Aggregation Database (gnomAD) 0.00017
Exome Aggregation Consortium (ExAC) 0.00044
Trans-Omics for Precision Medicine (TOPMed) 0.00014
Links
ClinGen: CA312178
dbSNP: rs201375579
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic/Likely pathogenic 3 criteria provided, multiple submitters, no conflicts Jan 9, 2019 RCV000185664.6
Likely pathogenic 1 criteria provided, single submitter - RCV001526622.1
Conflicting interpretations of pathogenicity 7 criteria provided, conflicting interpretations Oct 8, 2020 RCV000211538.14
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
ACADM - - GRCh38
GRCh37
463 491

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Feb 20, 2015)
criteria provided, single submitter
Method: clinical testing
Medium-chain acyl-coenzyme A dehydrogenase deficiency
(Autosomal recessive inheritance)
Allele origin: germline
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000268491.1
Submitted: (May 05, 2016)
Evidence details
Pathogenic
(Nov 16, 2018)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000238582.11
Submitted: (Jan 29, 2019)
Evidence details
Comment:
The D266G missense mutation has been reported previously in a patient who was detected by newborn screening, with follow-up biochemical studies consistent with MCAD deficiency … (more)
Pathogenic
(Oct 17, 2017)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000883327.1
Submitted: (Oct 10, 2018)
Evidence details
Comment:
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 … (more)
Likely pathogenic
(Dec 04, 2018)
criteria provided, single submitter
Method: clinical testing
Medium-chain acyl-coenzyme A dehydrogenase deficiency
Allele origin: germline
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota
Accession: SCV000891272.1
Submitted: (Mar 22, 2019)
Evidence details
Publications
PubMed (4)
Likely pathogenic
(Oct 31, 2018)
criteria provided, single submitter
Method: clinical testing
Medium-chain acyl-coenzyme A dehydrogenase deficiency
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000893476.1
Submitted: (Nov 14, 2018)
Evidence details
Publications
PubMed (1)
DOI: 10.1038/gim.2015.30
Likely pathogenic
(Jan 09, 2019)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001133291.2
Submitted: (Mar 06, 2020)
Evidence details
Publications
PubMed (10)
Comment:
The best available variant frequency is uninformative. Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Occurs in multiple … (more)
Uncertain significance
(Jan 13, 2018)
criteria provided, single submitter
Method: clinical testing
Medium-chain acyl-coenzyme A dehydrogenase deficiency
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV001255572.1
Submitted: (Feb 20, 2020)
Evidence details
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
Pathogenic
(Oct 08, 2020)
criteria provided, single submitter
Method: clinical testing
Medium-chain acyl-coenzyme A dehydrogenase deficiency
Allele origin: germline
Invitae
Accession: SCV000630296.6
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (6)
Comment:
This sequence change replaces aspartic acid with glycine at codon 266 of the ACADM protein (p.Asp266Gly). The aspartic acid residue is weakly conserved and there … (more)
Likely pathogenic
(-)
criteria provided, single submitter
Method: clinical testing
Epileptic spasm
Allele origin: paternal
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001737052.1
Submitted: (Jun 14, 2021)
Comment:
Compound heterozygous (other variant: PED8865.11), both variants inherited from one parent
Evidence details
Pathogenic
(Sep 16, 2020)
no assertion criteria provided
Method: clinical testing
Medium-chain acyl-coenzyme a dehydrogenase deficiency
Allele origin: germline
Natera, Inc.
Accession: SCV001461471.1
Submitted: (Dec 28, 2020)
Evidence details
Pathogenic
(Aug 17, 2021)
no assertion criteria provided
Method: clinical testing
Medium-chain acyl-coenzyme A dehydrogenase deficiency
Allele origin: germline
PerkinElmer Genomics
Accession: SCV002021018.1
Submitted: (Nov 19, 2021)
Evidence details

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: Findings from the Inborn Errors of Metabolism Collaborative. Bentler K Molecular genetics and metabolism 2016 PMID: 27477829
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Richards S Genetics in medicine : official journal of the American College of Medical Genetics 2015 PMID: 25741868
Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. Tabor HK American journal of human genetics 2014 PMID: 25087612
The domain-specific and temperature-dependent protein misfolding phenotype of variant medium-chain acyl-CoA dehydrogenase. Jank JM PloS one 2014 PMID: 24718418
MCAD deficiency in Denmark. Andresen BS Molecular genetics and metabolism 2012 PMID: 22542437
Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing. Smith EH Molecular genetics and metabolism 2010 PMID: 20434380
Dissection of biochemical borderline phenotypes in carriers and genetic variants of medium-chain acyl-CoA dehyrogenase deficiency: implications for newborn screening [corrected]. Maier EM Clinical genetics 2009 PMID: 19780764
Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screening. Maier EM Human molecular genetics 2009 PMID: 19224950
Mitochondrial fatty acid oxidation defects--remaining challenges. Gregersen N Journal of inherited metabolic disease 2008 PMID: 18836889
Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: a global perspective. Rhead WJ Journal of inherited metabolic disease 2006 PMID: 16763904
Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency. Maier EM Human mutation 2005 PMID: 15832312

Text-mined citations for rs201375579...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 04, 2021