NM_000016.6(ACADM):c.127G>A (p.Glu43Lys) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(2) (Last evaluated: Dec 12, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000176959.9

Allele description [Variation Report for NM_000016.6(ACADM):c.127G>A (p.Glu43Lys)]

NM_000016.6(ACADM):c.127G>A (p.Glu43Lys)

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.127G>A (p.Glu43Lys)
HGVS:
  • NC_000001.11:g.75732652G>A
  • NG_007045.2:g.13295G>A
  • NM_000016.6:c.127G>AMANE SELECT
  • NM_001127328.3:c.139G>A
  • NM_001286042.2:c.19G>A
  • NM_001286043.1:c.127G>A
  • NM_001286043.2:c.127G>A
  • NM_001286044.2:c.-259G>A
  • NP_000007.1:p.Glu43Lys
  • NP_001120800.1:p.Glu47Lys
  • NP_001272971.1:p.Glu7Lys
  • NP_001272972.1:p.Glu43Lys
  • NP_001272972.1:p.Glu43Lys
  • LRG_838t1:c.127G>A
  • LRG_838:g.13295G>A
  • LRG_838p1:p.Glu43Lys
  • NC_000001.10:g.76198337G>A
  • NM_000016.4:c.127G>A
  • NM_000016.5:c.127G>A
Protein change:
E43K
Links:
dbSNP: rs147559466
NCBI 1000 Genomes Browser:
rs147559466
Molecular consequence:
  • NM_001286044.2:c.-259G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000016.6:c.127G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127328.3:c.139G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286042.2:c.19G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286043.1:c.127G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286043.2:c.127G>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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000268433ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratoriescriteria provided, single submitter
Uncertain significance
(Feb 20, 2015)
germlineclinical testing

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

SCV000630279Invitaecriteria provided, single submitter
Uncertain significance
(Dec 12, 2019)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001257724Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely benign
(Apr 27, 2017)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown11not providednot providednot providednot providedclinical 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

Functional studies of 18 heterologously expressed medium-chain acyl-CoA dehydrogenase (MCAD) variants.

Koster KL, Sturm M, Herebian D, Smits SH, Spiekerkoetter U.

J Inherit Metab Dis. 2014 Nov;37(6):917-28. doi: 10.1007/s10545-014-9732-5. Epub 2014 Jun 26.

PubMed [citation]
PMID:
24966162
See all PubMed Citations (8)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000268433.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided11not providednot providedclinical testing
(GTR000500814.1)
PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided
(GTR000500814.1)
11not providednot providednot provided

From Invitae, SCV000630279.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces glutamic acid with lysine at codon 43 of the ACADM protein (p.Glu43Lys). 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 (rs147559466, ExAC 0.3%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in combination with the deleterious ACADM variant p.Lys329Glu in individuals affected with mild medium-chain acyl-CoA dehydrogenase deficiency (PMID: 20036593, 20434380, 22166308, 23028790, Invitae). Experimental studies have shown that this missense has a mild effect on ACADM enzymatic activity in vitro (PMID: 24966162). However this effect may not be sufficient to cause disease (PMID: 23028790). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV001257724.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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