NM_000016.5(ACADM):c.387+1del AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Clinical significance:Pathogenic (Last evaluated: Oct 14, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000169015.8

Allele description [Variation Report for NM_000016.5(ACADM):c.387+1del]

NM_000016.5(ACADM):c.387+1del

Gene:
ACADM:acyl-CoA dehydrogenase medium chain [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
1p31.1
Genomic location:
Preferred name:
NM_000016.5(ACADM):c.387+1del
HGVS:
  • NC_000001.10:g.76199310del
  • NC_000001.11:g.75733629del
  • NG_007045.2:g.14272del
  • NM_000016.5:c.387+1del
  • NM_000016.5:c.387del
  • NM_001127328.2:c.399+1del
  • NM_001286042.1:c.279+1del
  • NM_001286043.1:c.486+1del
  • NM_001286044.1:c.-100+707del
  • LRG_838t1:c.387+1del
  • LRG_838:g.14272del
  • NC_000001.10:g.76199310del
  • NC_000001.10:g.76199314del
  • NC_000001.10:g.76199314delG
  • NM_000016.4:c.387+1delG
  • NM_000016.4:c.387+1delG
  • NM_000016.5:c.387+1del
  • NM_000016.5:c.387+1delG
  • NM_000016.5:c.387del
Links:
dbSNP: rs786204424
NCBI 1000 Genomes Browser:
rs786204424
Molecular consequence:
  • NM_001286044.1:c.-100+707del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000016.5:c.387+1del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001127328.2:c.399+1del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001286042.1:c.279+1del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001286043.1:c.486+1del - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000220157Counsylno assertion criteria providedLikely pathogenic
(May 31, 2017)
unknownclinical testing

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

SCV000818999Invitaecriteria provided, single submitter
Pathogenic
(Oct 14, 2020)
germlineclinical testing

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

SCV001158671ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Jul 11, 2018)
germlineclinical testing

Citation Link,

SCV001361313Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(May 17, 2019)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State.

Arnold GL, Saavedra-Matiz CA, Galvin-Parton PA, Erbe R, Devincentis E, Kronn D, Mofidi S, Wasserstein M, Pellegrino JE, Levy PA, Adams DJ, Nichols M, Caggana M.

Mol Genet Metab. 2010 Mar;99(3):263-8. doi: 10.1016/j.ymgme.2009.10.188. Epub 2009 Nov 1.

PubMed [citation]
PMID:
20036593

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933
See all PubMed Citations (11)

Details of each submission

From Counsyl, SCV000220157.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000818999.4

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

Description

This sequence change affects a donor splice site in intron 5 of the ACADM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs754904305, ExAC 0.01%). This variant has been reported in combination with a second variant in individuals affected with medium-chain acyl-CoA dehydrogenase deficiency (PMID: 15832312, 23028790). This variant is also known as IVS5+1delG in the literature. ClinVar contains an entry for this variant (Variation ID: 188719). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACADM are known to be pathogenic (PMID: 16121256, 20434380). For these reasons, this variant has been classified as Pathogenic.

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

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001158671.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The ACADM c.387+1delG variant (rs786204424), also known as IVS 5+1delG, is reported in the literature in a compound heterozygous state in individuals affected with medium-chain acyl-coenzyme A dehydrogenase deficiency (Bentler 2016, Maier 2005, Sturm 2012). This variant is reported in ClinVar (Variation ID: 188719), and is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice donor site of intron 5, which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic. References: Bentler K et al. 221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: Findings from the Inborn Errors of Metabolism Collaborative. Mol Genet Metab. 2016 Sep;119(1-2):75-82. Maier EM et al. Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency. Hum Mutat. 2005 May;25(5):443-52. Sturm M et al. Functional effects of different medium-chain acyl-CoA dehydrogenase genotypes and identification of asymptomatic variants. PLoS One. 2012;7(9):e45110.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361313.1

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

Description

Variant summary: ACADM c.387+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. The variant is located in a run of Gs, which results in the deletion of the last G located in a splicing region which several computational tools predict the variant to shift splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251398 control chromosomes (gnomAD). c.387+1delG has been reported in the literature in individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Li_2019, Maier_2005, Sturm_2012, Waddell_2006, Bentler_2016). These data indicate that the variant is likely to be associated with disease. Sturm_2012 correlated residual MCAD activities with genotypes by measuring the octanoyl-CoA oxidation in lymphocytes and found the compound heterozygote patient to have a residual activity of 7%. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant once as pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Jun 14, 2021

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