NM_000016.6(ACADM):c.157C>T (p.Arg53Cys) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Mar 25, 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:: RCV000176961.31

Allele description [Variation Report for NM_000016.6(ACADM):c.157C>T (p.Arg53Cys)]

NM_000016.6(ACADM):c.157C>T (p.Arg53Cys)

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.157C>T (p.Arg53Cys)

HGVS:

NC_000001.11:g.75732682C>T
NG_007045.2:g.13325C>T
NM_000016.6:c.157C>TMANE SELECT
NM_001127328.3:c.169C>T
NM_001286042.2:c.49C>T
NM_001286043.2:c.157C>T
NM_001286044.2:c.-229C>T
NP_000007.1:p.Arg53Cys
NP_000007.1:p.Arg53Cys
NP_000007.1:p.Arg53Cys
NP_001120800.1:p.Arg57Cys
NP_001272971.1:p.Arg17Cys
NP_001272972.1:p.Arg53Cys
LRG_838t1:c.157C>T
LRG_838:g.13325C>T
LRG_838p1:p.Arg53Cys
NC_000001.10:g.76198367C>T
NM_000016.4:c.157C>T
NM_000016.5:c.157C>T
P11310:p.Arg53Cys

Protein change:

R17C

Links:

UniProtKB: P11310#VAR_000317; dbSNP: rs398123072

NCBI 1000 Genomes Browser:

rs398123072

Molecular consequence:

NM_001286044.2:c.-229C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000016.6:c.157C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127328.3:c.169C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001286042.2:c.49C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001286043.2:c.157C>T - missense variant - [Sequence Ontology: SO:0001583]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000268474	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 20, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000487011	Counsyl	no assertion criteria provided	Likely pathogenic (Sep 23, 2016)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15832312, 24623196, 8535441, 26947917, 20434380, 8102510, 19649258, 7730333
SCV000893467	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000943514	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15832312, 16737882, 20434380, 22796001, 24623196, 8102510, 26947917, 28492532
SCV002092800	Natera, Inc.	no assertion criteria provided	Pathogenic (May 3, 2017)	germline	clinical testing
SCV004216352	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 25, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	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

Citations

PubMed

Comparison between medium-chain acyl-CoA dehydrogenase mutant proteins overexpressed in bacterial and mammalian cells.

Jensen TG, Bross P, Andresen BS, Lund TB, Kristensen TJ, Jensen UB, Winther V, Kølvraa S, Gregersen N, Bolund L.

Hum Mutat. 1995;6(3):226-31.

PubMed [citation]

PMID:: 8535441

A novel tandem mass spectrometry method for rapid confirmation of medium- and very long-chain acyl-CoA dehydrogenase deficiency in newborns.

ter Veld F, Mueller M, Kramer S, Haussmann U, Herebian D, Mayatepek E, Laryea MD, Primassin S, Spiekerkoetter U.

PLoS One. 2009 Jul 30;4(7):e6449. doi: 10.1371/journal.pone.0006449.

PubMed [citation]

PMID:: 19649258
PMCID:: PMC2715108

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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000268474.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing (GTR000500814.1)	PubMed (1)

#	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	(GTR000500814.1)	2	not provided	not provided	not provided

From Counsyl, SCV000487011.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

#	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 Fulgent Genetics, Fulgent Genetics, SCV000893467.1

#	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 Invitae, SCV000943514.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 53 of the ACADM protein (p.Arg53Cys). This variant is present in population databases (rs398123072, gnomAD 0.02%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 8102510, 15832312, 16737882, 20434380, 22796001, 24623196). This variant is also known as R28C. ClinVar contains an entry for this variant (Variation ID: 92258). 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: 8102510, 26947917). 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 Natera, Inc., SCV002092800.1

#	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 Baylor Genetics, SCV004216352.2

#	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: Jul 23, 2024

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