NM_000016.6(ACADM):c.1124T>C (p.Ile375Thr) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Aug 5, 2022
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:: RCV000003772.5

Allele description [Variation Report for NM_000016.6(ACADM):c.1124T>C (p.Ile375Thr)]

NM_000016.6(ACADM):c.1124T>C (p.Ile375Thr)

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.1124T>C (p.Ile375Thr)

HGVS:

NC_000001.11:g.75761300T>C
NG_007045.2:g.41943T>C
NM_000016.6:c.1124T>CMANE SELECT
NM_001127328.3:c.1136T>C
NM_001286042.2:c.1016T>C
NM_001286043.2:c.1223T>C
NM_001286044.2:c.557T>C
NP_000007.1:p.Ile375Thr
NP_001120800.1:p.Ile379Thr
NP_001272971.1:p.Ile339Thr
NP_001272972.1:p.Ile408Thr
NP_001272973.1:p.Ile186Thr
LRG_838:g.41943T>C
NC_000001.10:g.76226985T>C
P11310:p.Ile375Thr

Protein change:

I186T; ILE375THR

Links:

UniProtKB: P11310#VAR_000327; OMIM: 607008.0004; dbSNP: rs121434275

NCBI 1000 Genomes Browser:

rs121434275

Molecular consequence:

NM_000016.6:c.1124T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127328.3:c.1136T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001286042.2:c.1016T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001286043.2:c.1223T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001286044.2:c.557T>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
SCV000023937	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 1991)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV003523289	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 5, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 1684086, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000023937

OMIM

no assertion criteria provided

Pathogenic
(Dec 1, 1991)

germline

literature only

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

SCV003523289

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 5, 2022)

germline

clinical testing

PubMed (2)
[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

Molecular survey of a prevalent mutation, 985A-to-G transition, and identification of five infrequent mutations in the medium-chain Acyl-CoA dehydrogenase (MCAD) gene in 55 patients with MCAD deficiency.

Yokota I, Coates PM, Hale DE, Rinaldo P, Tanaka K.

Am J Hum Genet. 1991 Dec;49(6):1280-91.

PubMed [citation]

PMID:: 1684086
PMCID:: PMC1686456

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From OMIM, SCV000023937.2

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

Description

Yokota et al. (1991) found a T-to-C transition at position 1124 in the ACADM gene as the responsible mutation in 1 of 110 mutant alleles.

#	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, SCV003523289.2

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

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 375 of the ACADM protein (p.Ile375Thr). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: 3589). This missense change has been observed in individual(s) with Medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 1684086). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121434275, gnomAD 0.1%).

#	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		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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