NM_000016.6(ACADM):c.584G>A (p.Gly195Glu) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 19, 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:: RCV003034578.3

Allele description [Variation Report for NM_000016.6(ACADM):c.584G>A (p.Gly195Glu)]

NM_000016.6(ACADM):c.584G>A (p.Gly195Glu)

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.584G>A (p.Gly195Glu)

HGVS:

NC_000001.11:g.75740095G>A
NG_007045.2:g.20738G>A
NM_000016.6:c.584G>AMANE SELECT
NM_001127328.3:c.596G>A
NM_001286042.2:c.476G>A
NM_001286043.2:c.683G>A
NM_001286044.2:c.17G>A
NP_000007.1:p.Gly195Glu
NP_000007.1:p.Gly195Glu
NP_001120800.1:p.Gly199Glu
NP_001272971.1:p.Gly159Glu
NP_001272972.1:p.Gly228Glu
NP_001272973.1:p.Gly6Glu
LRG_838t1:c.584G>A
LRG_838:g.20738G>A
LRG_838p1:p.Gly195Glu
NC_000001.10:g.76205780G>A
NM_000016.5:c.584G>A

Protein change:

G159E

Molecular consequence:

NM_000016.6:c.584G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127328.3:c.596G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286042.2:c.476G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286043.2:c.683G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286044.2:c.17G>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
SCV003328259	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 19, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 7603790, 16291504, 25940036, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003328259

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 19, 2023)

germline

clinical testing

PubMed (4)
[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

Medium chain acyl-CoA dehydrogenase deficiency in Pennsylvania: neonatal screening shows high incidence and unexpected mutation frequencies.

Ziadeh R, Hoffman EP, Finegold DN, Hoop RC, Brackett JC, Strauss AW, Naylor EW.

Pediatr Res. 1995 May;37(5):675-8.

PubMed [citation]

PMID:: 7603790

Medium-chain acyl-CoA dehydrogenase deficiency: genotype-biochemical phenotype correlations.

Waddell L, Wiley V, Carpenter K, Bennetts B, Angel L, Andresen BS, Wilcken B.

Mol Genet Metab. 2006 Jan;87(1):32-9. Epub 2005 Nov 15.

PubMed [citation]

PMID:: 16291504

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003328259.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 195 of the ACADM protein (p.Gly195Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ACADM-related conditions. ClinVar contains an entry for this variant (Variation ID: 2112467). 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 with a positive predictive value of 80%. This variant disrupts the p.Gly195 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7603790, 16291504, 25940036). 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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