NM_001270448.1(ACADVL):c.1147C>T (p.Arg383Trp) AND Very long chain acyl-CoA dehydrogenase deficiency

Clinical significance:Uncertain significance (Last evaluated: Nov 15, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000652041.1

Allele description [Variation Report for NM_001270448.1(ACADVL):c.1147C>T (p.Arg383Trp)]

NM_001270448.1(ACADVL):c.1147C>T (p.Arg383Trp)

Gene:
ACADVL:acyl-CoA dehydrogenase very long chain [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17p13.1
Genomic location:
Preferred name:
NM_001270448.1(ACADVL):c.1147C>T (p.Arg383Trp)
HGVS:
  • NC_000017.11:g.7224010C>T
  • NG_007975.1:g.9177C>T
  • NM_000018.3:c.1375C>T
  • NM_001270448.1:c.1147C>T
  • NP_000009.1:p.Arg459Trp
  • NP_001257377.1:p.Arg383Trp
  • NC_000017.10:g.7127329C>T
  • P49748:p.Arg459Trp
Protein change:
R383W
Links:
UniProtKB: P49748#VAR_000359; dbSNP: rs766742117
NCBI 1000 Genomes Browser:
rs766742117
Molecular consequence:
  • NM_000018.3:c.1375C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Very long chain acyl-CoA dehydrogenase deficiency (VLCAD)
Synonyms:
Long chain acyl-CoA dehydrogenase deficiency
Identifiers:
MedGen: C3887523; Orphanet: 26793; OMIM: 201475

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000773905Invitaecriteria provided, single submitter
Uncertain significance
(Nov 15, 2017)
germlineclinical testing

PubMed (8)
[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

Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency.

Andresen BS, Olpin S, Poorthuis BJ, Scholte HR, Vianey-Saban C, Wanders R, Ijlst L, Morris A, Pourfarzam M, Bartlett K, Baumgartner ER, deKlerk JB, Schroeder LD, Corydon TJ, Lund H, Winter V, Bross P, Bolund L, Gregersen N.

Am J Hum Genet. 1999 Feb;64(2):479-94.

PubMed [citation]
PMID:
9973285
PMCID:
PMC1377757

VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment.

Hoffmann L, Haussmann U, Mueller M, Spiekerkoetter U.

J Inherit Metab Dis. 2012 Mar;35(2):269-77. doi: 10.1007/s10545-011-9391-8. Epub 2011 Sep 20.

PubMed [citation]
PMID:
21932095
See all PubMed Citations (8)

Details of each submission

From Invitae, SCV000773905.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change replaces arginine with tryptophan at codon 459 of the ACADVL protein (p.Arg459Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs766742117, ExAC 0.01%). This variant has been reported in several individuals affected with very long chain acyl-CoA dehydrogenase deficiency but in whom no second allele was reported (PMID: 9973285, 21932095, 10738914). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Arg459Gln) has been determined to be pathogenic (PMID: 19327992, 23798014, 14517516, 23798014, 21429517). This suggests that the arginine residue is critical for ACADVL protein function and that other missense substitutions at this position may also be pathogenic. 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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