NM_000016.6(ACADM):c.253G>C (p.Gly85Arg) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 9, 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:: RCV001999884.4

Allele description [Variation Report for NM_000016.6(ACADM):c.253G>C (p.Gly85Arg)]

NM_000016.6(ACADM):c.253G>C (p.Gly85Arg)

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.253G>C (p.Gly85Arg)

HGVS:

NC_000001.11:g.75732889G>C
NG_007045.2:g.13532G>C
NM_000016.5:c.253G>C
NM_000016.6:c.253G>CMANE SELECT
NM_001127328.3:c.265G>C
NM_001286042.2:c.145G>C
NM_001286043.2:c.253G>C
NM_001286044.2:c.-133G>C
NP_000007.1:p.Gly85Arg
NP_001120800.1:p.Gly89Arg
NP_001272971.1:p.Gly49Arg
NP_001272972.1:p.Gly85Arg
LRG_838t1:c.253G>C
LRG_838:g.13532G>C
NC_000001.10:g.76198574G>C

Protein change:

G49R

Links:

dbSNP: rs398123075

NCBI 1000 Genomes Browser:

rs398123075

Molecular consequence:

NM_001286044.2:c.-133G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000016.6:c.253G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127328.3:c.265G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001286042.2:c.145G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001286043.2:c.253G>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
SCV002233602	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 9, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24294134, 25689098, 28492532
SCV003928462	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 5, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25689098, 24294134, 35629059, 33072938 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002233602

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 9, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV003928462

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 5, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Targeted metabolomics in the expanded newborn screening for inborn errors of metabolism.

Scolamiero E, Cozzolino C, Albano L, Ansalone A, Caterino M, Corbo G, di Girolamo MG, Di Stefano C, Durante A, Franzese G, Franzese I, Gallo G, Giliberti P, Ingenito L, Ippolito G, Malamisura B, Mazzeo P, Norma A, Ombrone D, Parenti G, Pellecchia S, Pecce R, et al.

Mol Biosyst. 2015 Jun;11(6):1525-35. doi: 10.1039/c4mb00729h.

PubMed [citation]

PMID:: 25689098

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV002233602.3

#	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. 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: 1452587). This missense change has been observed in individual(s) with clinical features of medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 24294134, 25689098). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 85 of the ACADM protein (p.Gly85Arg).

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003928462.1

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

Description

Variant summary: ACADM c.253G>C (p.Gly85Arg) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251180 control chromosomes (gnomAD). c.253G>C has been reported in the literature in several homozygous individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Catarzi_2013, Scolamiero_2015, Messina_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as 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: Feb 20, 2024

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