NM_000016.6(ACADM):c.797A>G (p.Asp266Gly) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Mar 27, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000211538.34

Allele description [Variation Report for NM_000016.6(ACADM):c.797A>G (p.Asp266Gly)]

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

Gene:

ACADM:acyl-CoA dehydrogenase medium chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p31.1

Genomic location:

Preferred name:

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

Other names:

p.D266G:GAC>GGC

HGVS:

NC_000001.11:g.75749507A>G
NG_007045.2:g.30150A>G
NM_000016.6:c.797A>GMANE SELECT
NM_000016.6:c.797A>G
NM_001127328.3:c.809A>G
NM_001286042.2:c.689A>G
NM_001286043.2:c.896A>G
NM_001286044.2:c.230A>G
NP_000007.1:p.Asp266Gly
NP_000007.1:p.Asp266Gly
NP_001120800.1:p.Asp270Gly
NP_001272971.1:p.Asp230Gly
NP_001272972.1:p.Asp299Gly
NP_001272972.1:p.Asp299Gly
NP_001272973.1:p.Asp77Gly
LRG_838t1:c.797A>G
LRG_838:g.30150A>G
LRG_838p1:p.Asp266Gly
NC_000001.10:g.76215192A>G
NM_000016.4:c.797A>G
NM_000016.5:c.797A>G
NM_001127328.1:c.809A>G
NM_001286043.1:c.896A>G

Protein change:

D230G

Links:

dbSNP: rs201375579

NCBI 1000 Genomes Browser:

rs201375579

Molecular consequence:

NM_000016.6:c.797A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127328.3:c.809A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001286042.2:c.689A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001286043.2:c.896A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001286044.2:c.230A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Medium-chain acyl-coenzyme A dehydrogenase deficiency (ACADMD)
Synonyms:: CARNITINE DEFICIENCY SECONDARY TO MEDIUM-CHAIN ACYL-CoA DEHYDROGENASE DEFICIENCY; MCADD; Medium chain acyl-CoA dehydrogenase deficiency
Identifiers:: MONDO: MONDO:0008721; MedGen: C0220710; Orphanet: 42; OMIM: 201450

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thioesterase family protein [Streptomyces sp. 71268]
thioesterase family protein [Streptomyces sp. 71268]
gi|2467927977|gnl|PRJNA907813|OYE22 0|gb|WEV29315.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000630296	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19780764, 22542437, 19224950, 24718418, 28492532
SCV000883327	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Oct 17, 2017)	germline	clinical testing	Citation Link,
SCV000891272	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 4, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22542437, 24718418, 19224950, 15832312, 25741868
SCV000893476	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001461471	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002570581	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jul 29, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 24718418, 20434380, 22542437, 15832312, 33580884, 23798014, 31836396, 18450854, 19224950 Citation Link,
SCV004212191	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 27, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Dissection of biochemical borderline phenotypes in carriers and genetic variants of medium-chain acyl-CoA dehyrogenase deficiency: implications for newborn screening [corrected].

Maier EM, Pongratz J, Muntau AC, Liebl B, Nennstiel-Ratzel U, Busch U, Fingerhut R, Olgemöller B, Roscher AA, Röschinger W.

Clin Genet. 2009 Aug;76(2):179-87. doi: 10.1111/j.1399-0004.2009.01217.x. Erratum in: Clin Genet. 2010 Mar;77(3):304.

PubMed [citation]

PMID:: 19780764

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (12)

PMC

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, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000630296.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000883327.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota, SCV000891272.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000893476.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001461471.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002570581.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004212191.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

Relating variation to medicine