NM_004453.3(ETFDH):c.1690+1G>T AND Glutaric aciduria, type 2

Clinical significance:Uncertain significance (Last evaluated: Oct 5, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000634895.1

Allele description [Variation Report for NM_004453.3(ETFDH):c.1690+1G>T]

NM_004453.3(ETFDH):c.1690+1G>T

Gene:
ETFDH:electron transfer flavoprotein dehydrogenase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
4q32.1
Genomic location:
Preferred name:
NM_004453.3(ETFDH):c.1690+1G>T
HGVS:
  • NC_000004.12:g.158706851G>T
  • NG_007078.2:g.39510G>T
  • NM_004453.3:c.1690+1G>T
  • NC_000004.11:g.159628003G>T
Links:
dbSNP: rs917285990
NCBI 1000 Genomes Browser:
rs917285990
Molecular consequence:
  • NM_004453.3:c.1690+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
Glutaric aciduria, type 2 (MADD)
Synonyms:
GA II; GLUTARIC ACIDURIA II; Multiple Acyl Coenzyme A Dehydrogenase Deficiency
Identifiers:
MedGen: C0268596; Orphanet: 26791; OMIM: 231680

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000756262Invitaecriteria provided, single submitter
Uncertain significance
(Oct 5, 2017)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Characterization of a mutation that abolishes quinone reduction by electron transfer flavoprotein-ubiquinone oxidoreductase.

Beard SE, Goodman SI, Bemelen K, Frerman FE.

Hum Mol Genet. 1995 Feb;4(2):157-61.

PubMed [citation]
PMID:
7757062

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.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000756262.1

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

Description

This sequence change affects a donor splice site in the last intron (intron 12) of the ETFDH gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in combination with a pathogenic variant in the ETFDH gene in an individual affected with glutaric aciduria II (PMID: 7757062). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant causes the skipping of exon 12, resulting in the disruption of the last 128 residues of the ETFDH protein. Expression of this variant in yeast cells have been shown to result in a protein with no quinone reductase activity (PMID: 7757062). 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

Last Updated: Mar 30, 2019

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