NM_000016.6(ACADM):c.127G>A (p.Glu43Lys) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(3);Uncertain significance(3) (Last evaluated: Dec 8, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
6 submissions [Details]
Record status:
current
Accession:
RCV000077881.15

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_000016.5:c.127G>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_000007.1:p.Glu43Lys
  • 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
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_000016.5:c.127G>A - missense variant - [Sequence Ontology: SO:0001583]
  • 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]
Observations:
17

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000228749EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
Pathogenic
(Aug 6, 2012)
germlineclinical testing

Citation Link,

SCV000281073Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinicscriteria provided, single submitter
Pathogenic
(Mar 30, 2015)
germlineclinical testing

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

SCV000693955Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(May 26, 2017)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000884944ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratoriescriteria provided, single submitter
Uncertain significance
(Jul 26, 2017)
germlineclinical testing

Citation Link,

SCV001147312CeGaT Praxis fuer Humangenetik Tuebingencriteria provided, single submitter
Uncertain significance
(Dec 1, 2019)
germlineclinical testing

Citation Link,

SCV001715538Mayo Clinic Laboratories, Mayo Cliniccriteria provided, single submitter
Pathogenic
(Dec 8, 2020)
germlineclinical testing

PubMed (18)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown14not providednot providednot providednot providedclinical testing
not providedgermlineyes3not providednot providednot providednot providedclinical testing

Citations

PubMed

Rapid, comprehensive screening of the human medium chain acyl-CoA dehydrogenase gene.

McKinney JT, Longo N, Hahn SH, Matern D, Rinaldo P, Strauss AW, Dobrowolski SF.

Mol Genet Metab. 2004 Jun;82(2):112-20.

PubMed [citation]
PMID:
15171998

An informatics approach to analyzing the incidentalome.

Berg JS, Adams M, Nassar N, Bizon C, Lee K, Schmitt CP, Wilhelmsen KC, Evans JP.

Genet Med. 2013 Jan;15(1):36-44. doi: 10.1038/gim.2012.112. Epub 2012 Sep 20.

PubMed [citation]
PMID:
22995991
PMCID:
PMC3538953
See all PubMed Citations (18)

Details of each submission

From EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000228749.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided12not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided12not providednot providednot provided

From Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics, SCV000281073.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot provided0.003053not providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000693955.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: The ACADM c.127G>A (p.Glu43Lys) variant involves the alteration of a conserved nucleotide, is located in Acyl-CoA dehydrogenase/oxidase, N-terminal domain of the protein (InterPro) and is predicted to be benign by 2/4 in silico tools (SNPsandGO not captured due to low reliability index). This variant was found in 272/120842 control chromosomes from ExAC (including one homozygote) at an allele frequency of 0.225% which does not exceed the estimated maximal expected allele frequency of a pathogenic ACADM variant of 0.542%. This variant has been reported in several subjects during newborn screening programs in compound heterozygous with another pathogenic variant c.985A>G (Smith_2010, Sturm_2012, Catarzi_2013). However, they were biochemically indistinguishable from MCAD carriers, suggesting this variant is likely innocuous. In addition, asymptomatic father of an MCAD deficient child, homozygous for the c.985A>G mutation, carried the c.127G>A mutation on one allele and the c.985A>G mutation on the other (Sturm_2012). He had never been symptomatic despite many infectious illnesses in the past. Enzymatic measurement in lymphocytes from a subject who was compound heterozygous for this variant and c.985A>G showed 56% of normal activity, clearly in the range of proven heterozygotes that do not have a risk of symptomatic disease, unless in a situation of possible synergistic heterozygosity (Sturm_2012). Functional study (Koster_2014) showed variant with comparable to WT specificity to substrates C8-CoA and C12-CoA, and ~60% WT level of specificity to substrate C10-coA. Variant showed 43% relative residual octanoyl-CoA oxidation activities to WT, and the residual activity of variant was improved by co-overexpression with molecular chaperones and variant to >100% of WT level. In response to temprature change, variant showed a similar decrease in residual activity as that observed for the wild type. These data suggested that variant of interest is a mild MCAD variant. This variant has also been reported in a clinically affected case in compound heterozygous state with c.985A>G (Catarzi_2013); details of clinical manifestations in the patient are not provided. Of three labs that submitted this variant in ClinVar, two have classified it as pathogenic and one has classified it as uncertain significance. One of the labs also reports de novo origin of this variant. To summarize, this variant leads to very mild functional impairment which may not be sufficient to cause symptomatic disease in compound heterozygous state with other pathogenic/likely pathogenic variants and in homozygous state as well. However, it may still have a synergistic or modifier effect. Therefore, this variant is currently classified as Variant of Unknown Significance.

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000884944.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From CeGaT Praxis fuer Humangenetik Tuebingen, SCV001147312.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided3not providednot providednot provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001715538.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (18)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided2not providednot providednot provided

Last Updated: Nov 20, 2021

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