NM_000016.6(ACADM):c.592G>A (p.Ala198Thr) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 10, 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:: RCV001050144.9

Allele description [Variation Report for NM_000016.6(ACADM):c.592G>A (p.Ala198Thr)]

NM_000016.6(ACADM):c.592G>A (p.Ala198Thr)

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.592G>A (p.Ala198Thr)

HGVS:

NC_000001.11:g.75740103G>A
NG_007045.2:g.20746G>A
NM_000016.6:c.592G>AMANE SELECT
NM_001127328.3:c.604G>A
NM_001286042.2:c.484G>A
NM_001286043.2:c.691G>A
NM_001286044.2:c.25G>A
NP_000007.1:p.Ala198Thr
NP_001120800.1:p.Ala202Thr
NP_001272971.1:p.Ala162Thr
NP_001272972.1:p.Ala231Thr
NP_001272973.1:p.Ala9Thr
LRG_838t1:c.592G>A
LRG_838:g.20746G>A
NC_000001.10:g.76205788G>A
NM_000016.5:c.592G>A

Protein change:

A162T

Links:

dbSNP: rs1647485086

NCBI 1000 Genomes Browser:

rs1647485086

Molecular consequence:

NM_000016.6:c.592G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127328.3:c.604G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286042.2:c.484G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286043.2:c.691G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286044.2:c.25G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001214240	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 10, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001461464	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001214240

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 10, 2023)

germline

clinical testing

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

SCV001461464

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Sep 16, 2020)

germline

clinical testing

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

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001214240.5

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

Description

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: 846754). This missense change has been observed in individual(s) with clinical features of medium chain acyl-CoA dehydrogenase deficiency (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 198 of the ACADM protein (p.Ala198Thr).

#	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 Natera, Inc., SCV001461464.1

#	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

Last Updated: Sep 29, 2024

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