NM_000016.6(ACADM):c.447G>T (p.Met149Ile) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jun 3, 2023
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:: RCV000211526.19

Allele description [Variation Report for NM_000016.6(ACADM):c.447G>T (p.Met149Ile)]

NM_000016.6(ACADM):c.447G>T (p.Met149Ile)

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.447G>T (p.Met149Ile)

HGVS:

NC_000001.11:g.75734850G>T
NG_007045.2:g.15493G>T
NM_000016.6:c.447G>TMANE SELECT
NM_001127328.3:c.459G>T
NM_001286042.2:c.339G>T
NM_001286043.2:c.546G>T
NM_001286044.2:c.-100+1928G>T
NP_000007.1:p.Met149Ile
NP_000007.1:p.Met149Ile
NP_001120800.1:p.Met153Ile
NP_001272971.1:p.Met113Ile
NP_001272972.1:p.Met182Ile
LRG_838t1:c.447G>T
LRG_838:g.15493G>T
LRG_838p1:p.Met149Ile
NC_000001.10:g.76200535G>T
NM_000016.4:c.447G>T
NM_000016.5:c.447G>T
P11310:p.Met149Ile

Protein change:

M113I

Links:

UniProtKB: P11310#VAR_000319; dbSNP: rs121434277

NCBI 1000 Genomes Browser:

rs121434277

Molecular consequence:

NM_001286044.2:c.-100+1928G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000016.6:c.447G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127328.3:c.459G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001286042.2:c.339G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001286043.2:c.546G>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
SCV000268442	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Likely pathogenic (Jul 22, 2019)	germline	clinical testing	Citation Link,
SCV001219803	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 3, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 1684086, 9158144, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000268442

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Likely pathogenic
(Jul 22, 2019)

germline

clinical testing

Citation Link,

SCV001219803

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 3, 2023)

germline

clinical testing

PubMed (3)
[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	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

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

The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype?

Andresen BS, Bross P, Udvari S, Kirk J, Gray G, Kmoch S, Chamoles N, Knudsen I, Winter V, Wilcken B, Yokota I, Hart K, Packman S, Harpey JP, Saudubray JM, Hale DE, Bolund L, Kølvraa S, Gregersen N.

Hum Mol Genet. 1997 May;6(5):695-707.

PubMed [citation]

PMID:: 9158144

See all PubMed Citations (3)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000268442.2

#	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 Counsyl, SCV000800615.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001219803.5

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met149 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1684086, 9158144; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 226059). This missense change has been observed in individuals with MCAD deficiency (PMID: 1684086, 9158144; Invitae). This variant is present in population databases (rs121434277, gnomAD 0.003%). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 149 of the ACADM protein (p.Met149Ile).

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000800615	Counsyl	flagged submission Reason: Claim with insufficient supporting evidence Notes: None (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Nov 3, 2017)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000800615

Counsyl

flagged submission

Reason: Claim with insufficient supporting evidence

Notes: None

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(Nov 3, 2017)

unknown

clinical testing

Citation Link

Last Updated: Sep 29, 2024

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