NM_004453.3(ETFDH):c.1448C>T (p.Pro483Leu) AND Glutaric aciduria, type 2

Clinical significance:Likely pathogenic (Last evaluated: Sep 21, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000634896.2

Allele description [Variation Report for NM_004453.3(ETFDH):c.1448C>T (p.Pro483Leu)]

NM_004453.3(ETFDH):c.1448C>T (p.Pro483Leu)

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.1448C>T (p.Pro483Leu)
HGVS:
  • NC_000004.12:g.158706351C>T
  • NG_007078.2:g.39010C>T
  • NM_004453.3:c.1448C>T
  • NP_004444.2:p.Pro483Leu
  • NC_000004.11:g.159627503C>T
  • Q16134:p.Pro483Leu
Protein change:
P483L; PRO483LEU
Links:
UniProtKB: Q16134#VAR_075457; OMIM: 231675.0008; dbSNP: rs377656387
NCBI 1000 Genomes Browser:
rs377656387
Molecular consequence:
  • NM_004453.3:c.1448C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000756264Invitaecriteria provided, single submitter
Likely pathogenic
(Sep 21, 2017)
germlineclinical testing

PubMed (5)
[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

Molecular mechanisms of riboflavin responsiveness in patients with ETF-QO variations and multiple acyl-CoA dehydrogenation deficiency.

Cornelius N, Frerman FE, Corydon TJ, Palmfeldt J, Bross P, Gregersen N, Olsen RK.

Hum Mol Genet. 2012 Aug 1;21(15):3435-48. doi: 10.1093/hmg/dds175. Epub 2012 May 18.

PubMed [citation]
PMID:
22611163

ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency.

Olsen RK, Olpin SE, Andresen BS, Miedzybrodzka ZH, Pourfarzam M, Merinero B, Frerman FE, Beresford MW, Dean JC, Cornelius N, Andersen O, Oldfors A, Holme E, Gregersen N, Turnbull DM, Morris AA.

Brain. 2007 Aug;130(Pt 8):2045-54. Epub 2007 Jun 20.

PubMed [citation]
PMID:
17584774
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000756264.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces proline with leucine at codon 483 of the ETFDH protein (p.Pro483Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs377656387, ExAC 0.006%). This variant has been reported in individuals affected with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (PMID: 17412732, 17584774, 24190796). ClinVar contains an entry for this variant (Variation ID: 31602). Experimental studies have shown that this missense variant decreases protein stability and activity in cultured cells (PMID: 17584774, 22611163). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Mar 30, 2019

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