NM_000016.6(ACADM):c.842G>C (p.Arg281Thr) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 8, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000003779.4

Allele description [Variation Report for NM_000016.6(ACADM):c.842G>C (p.Arg281Thr)]

NM_000016.6(ACADM):c.842G>C (p.Arg281Thr)

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.842G>C (p.Arg281Thr)

Other names:

R256T

HGVS:

NC_000001.11:g.75749552G>C
NG_007045.2:g.30195G>C
NM_000016.6:c.842G>CMANE SELECT
NM_001127328.3:c.854G>C
NM_001286042.2:c.734G>C
NM_001286043.2:c.941G>C
NM_001286044.2:c.275G>C
NP_000007.1:p.Arg281Thr
NP_001120800.1:p.Arg285Thr
NP_001272971.1:p.Arg245Thr
NP_001272972.1:p.Arg314Thr
NP_001272973.1:p.Arg92Thr
LRG_838:g.30195G>C
NC_000001.10:g.76215237G>C
P11310:p.Arg281Thr

Protein change:

R245T; ARG256THR

Links:

UniProtKB: P11310#VAR_013700; OMIM: 607008.0013; dbSNP: rs121434282

NCBI 1000 Genomes Browser:

rs121434282

Molecular consequence:

NM_000016.6:c.842G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127328.3:c.854G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001286042.2:c.734G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001286043.2:c.941G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001286044.2:c.275G>C - 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
SCV000023944	OMIM	no assertion criteria provided	Pathogenic (Jun 1, 2001)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004282185	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 8, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11486912, 15915086, 26947917, 27856190, 16128823, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000023944

OMIM

no assertion criteria provided

Pathogenic
(Jun 1, 2001)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV004282185

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 8, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Compound heterozygosity in four asymptomatic siblings with medium-chain acyl-CoA dehydrogenase deficiency.

Albers S, Levy HL, Irons M, Strauss AW, Marsden D.

J Inherit Metab Dis. 2001 Jun;24(3):417-8. No abstract available.

PubMed [citation]

PMID:: 11486912

Genotypic differences of MCAD deficiency in the Asian population: novel genotype and clinical symptoms preceding newborn screening notification.

Ensenauer R, Winters JL, Parton PA, Kronn DF, Kim JW, Matern D, Rinaldo P, Hahn SH.

Genet Med. 2005 May-Jun;7(5):339-43.

PubMed [citation]

PMID:: 15915086

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000023944.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Albers et al. (2001) reported a G-to-C transversion at nucleotide 842 in the ACADM gene, resulting in an arg256-to-thr substitution. This mutation was found in compound heterozygosity with the lys304-to-glu mutation (607008.0001) in 4 asymptomatic sibs, ranging in age from 1 to 9 years, with MCAD deficiency (201450). The proband was identified because of expanded newborn screening using tandem mass spectrometry. Albers et al. (2001) suggested that this mutation may have a mild or benign clinical phenotype and that it is important to screen older unscreened sibs of all infants diagnosed by expanded newborn screening.

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

From Invitae, SCV004282185.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This variant is present in population databases (rs121434282, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 281 of the ACADM protein (p.Arg281Thr). This missense change has been observed in individual(s) with medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 11486912). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg281 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15915086, 26947917, 27856190). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ACADM function (PMID: 16128823). 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. ClinVar contains an entry for this variant (Variation ID: 3596). This variant is also known as R256T.

#	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

Last Updated: Apr 15, 2024

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