NM_000016.6(ACADM):c.728G>A (p.Arg243Gln) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Feb 12, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000211470.16

Allele description [Variation Report for NM_000016.6(ACADM):c.728G>A (p.Arg243Gln)]

NM_000016.6(ACADM):c.728G>A (p.Arg243Gln)

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.728G>A (p.Arg243Gln)

HGVS:

NC_000001.11:g.75749438G>A
NG_007045.2:g.30081G>A
NM_000016.6:c.728G>AMANE SELECT
NM_001127328.3:c.740G>A
NM_001286042.2:c.620G>A
NM_001286043.2:c.827G>A
NM_001286044.2:c.161G>A
NP_000007.1:p.Arg243Gln
NP_001120800.1:p.Arg247Gln
NP_001272971.1:p.Arg207Gln
NP_001272972.1:p.Arg276Gln
NP_001272973.1:p.Arg54Gln
LRG_838:g.30081G>A
NC_000001.10:g.76215123G>A
NM_000016.4:c.728G>A

Protein change:

R207Q

Links:

dbSNP: rs373852490

NCBI 1000 Genomes Browser:

rs373852490

Molecular consequence:

NM_000016.6:c.728G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127328.3:c.740G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286042.2:c.620G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286043.2:c.827G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286044.2:c.161G>A - 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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thioesterase family protein [Burkholderia anthina]
thioesterase family protein [Burkholderia anthina]
gi|1951803527|gnl|PRJNA686829|JFN94 0|gb|QQK05371.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000268478	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 20, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002092850	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 29, 2020)	germline	clinical testing
SCV003523314	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 24, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22542437, 24294134, 28492532
SCV004216363	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 12, 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	1	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

MCAD deficiency in Denmark.

Andresen BS, Lund AM, Hougaard DM, Christensen E, Gahrn B, Christensen M, Bross P, Vested A, Simonsen H, Skogstrand K, Olpin S, Brandt NJ, Skovby F, Nørgaard-Pedersen B, Gregersen N.

Mol Genet Metab. 2012 Jun;106(2):175-88. doi: 10.1016/j.ymgme.2012.03.018. Epub 2012 Apr 4.

PubMed [citation]

PMID:: 22542437

Medium-chain acyl-CoA deficiency: outlines from newborn screening, in silico predictions, and molecular studies.

Catarzi S, Caciotti A, Thusberg J, Tonin R, Malvagia S, la Marca G, Pasquini E, Cavicchi C, Ferri L, Donati MA, Baronio F, Guerrini R, Mooney SD, Morrone A.

ScientificWorldJournal. 2013;2013:625824. doi: 10.1155/2013/625824.

PubMed [citation]

PMID:: 24294134
PMCID:: PMC3833120

See all PubMed Citations (4)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000268478.1

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

From Natera, Inc., SCV002092850.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003523314.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 243 of the ACADM protein (p.Arg243Gln). This variant is present in population databases (rs373852490, gnomAD 0.008%). This missense change has been observed in individual(s) with medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 22542437, 24294134). ClinVar contains an entry for this variant (Variation ID: 226088). 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%. 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 Baylor Genetics, SCV004216363.2

#	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: Sep 29, 2024

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