NM_000016.5(ACADM):c.757G>A (p.Glu253Lys) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Dec 20, 2017
Review status:: criteria provided, conflicting classifications

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:: RCV000211500.1

Allele description

NM_000016.5(ACADM):c.757G>A (p.Glu253Lys)

Gene:

ACADM:acyl-CoA dehydrogenase medium chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p31.1

Genomic location:

Preferred name:

NM_000016.5(ACADM):c.757G>A (p.Glu253Lys)

HGVS:

NC_000001.11:g.75749467G>A
NG_007045.2:g.30110G>A
NM_000016.5:c.757G>A
NP_000007.1:p.Glu253Lys
NC_000001.10:g.76215152G>A
NM_000016.4:c.757G>A

Protein change:

E253K

Links:

dbSNP: rs768884003

NCBI 1000 Genomes Browser:

rs768884003

Allele Frequency:

0.00001(A)

Molecular consequence:

NM_000016.5:c.757G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCAD)
Synonyms:: CARNITINE DEFICIENCY SECONDARY TO MEDIUM-CHAIN ACYL-CoA DEHYDROGENASE DEFICIENCY
Identifiers:: MedGen: C0220710; Orphanet: 42; OMIM: 201450

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000268436	ARUP Laboratories, Molecular Genetics and Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 20, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000754915	Invitae	criteria provided, single submitter (Nykamp K et al. (Genet Med 2017))	Uncertain significance (Dec 20, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000268436

ARUP Laboratories, Molecular Genetics and Genomics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 20, 2015)

germline

clinical testing

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

SCV000754915

Invitae

criteria provided, single submitter

(Nykamp K et al. (Genet Med 2017))

Uncertain significance
(Dec 20, 2017)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, SCV000268436.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing (GTR000500814.1)	PubMed (1)

#	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	(GTR000500814.1)	2	not provided	not provided	not provided

From Invitae, SCV000754915.1

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

Description

This sequence change replaces glutamic acid with lysine at codon 253 of the ACADM protein (p.Glu253Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs768884003, ExAC 0.009%). This variant has not been reported in the literature in individuals with ACADM-related disease. ClinVar contains an entry for this variant (Variation ID: 226054). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Jul 21, 2018

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