NM_000016.6(ACADM):c.797A>G (p.Asp266Gly) AND not provided

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jan 9, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000185664.6

Allele description [Variation Report for NM_000016.6(ACADM):c.797A>G (p.Asp266Gly)]

NM_000016.6(ACADM):c.797A>G (p.Asp266Gly)

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.797A>G (p.Asp266Gly)
Other names:
p.D266G:GAC>GGC
HGVS:
  • NC_000001.11:g.75749507A>G
  • NG_007045.2:g.30150A>G
  • NM_000016.6:c.797A>GMANE SELECT
  • NM_000016.6:c.797A>G
  • NM_001127328.3:c.809A>G
  • NM_001286042.2:c.689A>G
  • NM_001286043.2:c.896A>G
  • NM_001286044.2:c.230A>G
  • NP_000007.1:p.Asp266Gly
  • NP_000007.1:p.Asp266Gly
  • NP_001120800.1:p.Asp270Gly
  • NP_001272971.1:p.Asp230Gly
  • NP_001272972.1:p.Asp299Gly
  • NP_001272972.1:p.Asp299Gly
  • NP_001272973.1:p.Asp77Gly
  • LRG_838t1:c.797A>G
  • LRG_838:g.30150A>G
  • LRG_838p1:p.Asp266Gly
  • NC_000001.10:g.76215192A>G
  • NM_000016.4:c.797A>G
  • NM_000016.5:c.797A>G
  • NM_001127328.1:c.809A>G
  • NM_001286043.1:c.896A>G
Protein change:
D230G
Links:
dbSNP: rs201375579
NCBI 1000 Genomes Browser:
rs201375579
Molecular consequence:
  • NM_000016.6:c.797A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127328.3:c.809A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286042.2:c.689A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286043.2:c.896A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286044.2:c.230A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000238582GeneDxcriteria provided, single submitter
Pathogenic
(Nov 16, 2018)
germlineclinical testing

Citation Link,

SCV000883327ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Oct 17, 2017)
germlineclinical testing

Citation Link,

SCV001133291Quest Diagnostics Nichols Institute San Juan Capistranocriteria provided, single submitter
Likely pathogenic
(Jan 9, 2019)
germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: a global perspective.

Rhead WJ.

J Inherit Metab Dis. 2006 Apr-Jun;29(2-3):370-7. Review.

PubMed [citation]
PMID:
16763904

Mitochondrial fatty acid oxidation defects--remaining challenges.

Gregersen N, Andresen BS, Pedersen CB, Olsen RK, Corydon TJ, Bross P.

J Inherit Metab Dis. 2008 Oct;31(5):643-57. doi: 10.1007/s10545-008-0990-y. Epub 2008 Oct 7.

PubMed [citation]
PMID:
18836889
See all PubMed Citations (11)

Details of each submission

From GeneDx, SCV000238582.11

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

Description

The D266G missense mutation has been reported previously in a patient who was detected by newborn screening, with follow-up biochemical studies consistent with MCAD deficiency (Maier et al., 2005). Functional studies under thermal stress found that D266G resulted in protein misfolding similar to the K329E mutation and may therefore be classified as just as severe (Jank et al., 2014). The variant is found in FAO-MET panel(s).

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000883327.1

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

Description

The ACADM c.797A>G, p.Asp266Gly (rs201375579), also known as D241G, has been reported in an individual with medium chain acyl-CoA dehydrogenase deficiency, in-trans with the common p.Lys329Glu pathogenic variant (Maier 2005). Functional characterization of the variant protein indicates reduced enzymatic activity and protein stability, likely due to the defects in monomer folding and tetramer formation (Jank 2014, Maier 2009). The variant is classified as pathogenic in ClinVar (Variation ID: 203540), and observed in the general population databases at a frequency of 0.08 percent in the Exome Variant Server (1/13006 alleles), and 0.03 percent in the Genome Aggregation Database (73/246234 alleles). Based on the above information, the variant is classified as pathogenic. References: Jank J et al. The domain-specific and temperature-dependent protein misfolding phenotype of variant medium-chain acyl-CoA dehydrogenase. PLoS One. 2014; 9(4):e93852. Maier E et al. Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency. Hum Mutat. 2005; 25(5):443-52. Maier E et al. Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screening. Hum Mol Genet. 2009; 18(9):1612-23.

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001133291.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

The best available variant frequency is uninformative. Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.

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

Last Updated: Dec 4, 2021

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