NM_000016.6(ACADM):c.555T>G (p.Ile185Met) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 18, 2019
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:: RCV001209720.7

Allele description [Variation Report for NM_000016.6(ACADM):c.555T>G (p.Ile185Met)]

NM_000016.6(ACADM):c.555T>G (p.Ile185Met)

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.555T>G (p.Ile185Met)

HGVS:

NC_000001.11:g.75740066T>G
NG_007045.2:g.20709T>G
NM_000016.6:c.555T>GMANE SELECT
NM_001127328.3:c.567T>G
NM_001286042.2:c.447T>G
NM_001286043.2:c.654T>G
NM_001286044.2:c.-13T>G
NP_000007.1:p.Ile185Met
NP_001120800.1:p.Ile189Met
NP_001272971.1:p.Ile149Met
NP_001272972.1:p.Ile218Met
LRG_838t1:c.555T>G
LRG_838:g.20709T>G
NC_000001.10:g.76205751T>G
NM_000016.5:c.555T>G

Protein change:

I149M

Links:

dbSNP: rs1647481193

NCBI 1000 Genomes Browser:

rs1647481193

Molecular consequence:

NM_001286044.2:c.-13T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000016.6:c.555T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127328.3:c.567T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001286042.2:c.447T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001286043.2:c.654T>G - 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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Mus musculus phospholipid phosphatase 7 (inactive) (Plpp7), transcript variant 1...
Mus musculus phospholipid phosphatase 7 (inactive) (Plpp7), transcript variant 1, mRNA
gi|1243938421|ref|NM_145521.4|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001381167	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 18, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27856190, 20434380, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001381167

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 18, 2019)

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

Citations

PubMed

Screening of MCAD deficiency in Japan: 16years' experience of enzymatic and genetic evaluation.

Tajima G, Hara K, Tsumura M, Kagawa R, Okada S, Sakura N, Hata I, Shigematsu Y, Kobayashi M.

Mol Genet Metab. 2016 Dec;119(4):322-328. doi: 10.1016/j.ymgme.2016.10.007. Epub 2016 Oct 21.

PubMed [citation]

PMID:: 27856190

Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing.

Smith EH, Thomas C, McHugh D, Gavrilov D, Raymond K, Rinaldo P, Tortorelli S, Matern D, Highsmith WE, Oglesbee D.

Mol Genet Metab. 2010 Jul;100(3):241-50. doi: 10.1016/j.ymgme.2010.04.001. Epub 2010 Apr 8.

PubMed [citation]

PMID:: 20434380

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001381167.4

#	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 isoleucine with methionine at codon 185 of the ACADM protein (p.Ile185Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another ACADM variant in an individual affected with medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 27856190). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Ile185 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20434380). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#	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: Sep 29, 2024

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