NM_000018.4(ACADVL):c.1316G>A (p.Gly439Asp) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(2);Uncertain significance(1) (Last evaluated: Jan 29, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000185723.4

Allele description [Variation Report for NM_000018.4(ACADVL):c.1316G>A (p.Gly439Asp)]

NM_000018.4(ACADVL):c.1316G>A (p.Gly439Asp)

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_000018.4(ACADVL):c.1316G>A (p.Gly439Asp)
Other names:
p.G439D:GGT>GAT
HGVS:
  • NC_000017.11:g.7223859G>A
  • NG_007975.1:g.9026G>A
  • NM_000018.4:c.1316G>A
  • NM_001033859.2:c.1250G>A
  • NM_001270448.1:c.1088G>A
  • NP_000009.1:p.Gly439Asp
  • NP_001029031.1:p.Gly417Asp
  • NP_001257377.1:p.Gly363Asp
  • NC_000017.10:g.7127178G>A
  • NM_000018.2:c.1316G>A
  • NM_000018.3:c.1316G>A
  • NM_001033859.1:c.1250G>A
Protein change:
G363D
Links:
dbSNP: rs533055438
NCBI 1000 Genomes Browser:
rs533055438
Molecular consequence:
  • NM_000018.3:c.1316G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
3

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000238649GeneDxcriteria provided, single submitter
Pathogenic
(Jul 17, 2017)
germlineclinical testing

Citation Link,

SCV000700260EGL Genetic Diagnostics,Eurofins Clinical Diagnosticscriteria provided, single submitter
Uncertain significance
(Jan 31, 2017)
germlineclinical testing

Citation Link,

SCV000884949ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Jan 29, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown3not providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000238649.13

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

Description

The G439D pathogenic variant in the ACADVL gene has been reported previously in association with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Gobin-Limballe et al., 2007; Schiff et al., 2013; Pena et al., 2016). Expression of G439D in e. coli found that enzyme activity associated with this variant was undetectable (Schiff et al., 2013). The G439D variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G439D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret G439D to be a pathogenic variant.

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

From EGL Genetic Diagnostics,Eurofins Clinical Diagnostics, SCV000700260.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided3not providednot providednot provided

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV000884949.1

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

Description

The ACADVL c.1316G>A; p.Gly439Asp variant (rs533055438) is reported in the literature in individuals diagnosed with VLCAD deficiency, who are heterozygous for another ACADVL variant (Gobin-Limballe 2010, Pena 2016, Schiff 2013). Cultured fibroblasts from an individual carrying p.Gly439Asp and p.Met443Arg, showed no detectable VLCAD activity (Schiff 2013). Furthermore, functional analysis of p.Gly439Asp expressed using an in vitro prokaryotic system yielded no activity, even though protein of the correct size was detected by Western blot (Schiff 2013). The p.Gly439Asp variant is reported as pathogenic in ClinVar (Variation ID: 203582), and found in the general population with a low frequency of 0.002% (6/277134 alleles) in the Genome Aggregation Database. The glycine at codon 439 is highly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be deleterious. Based on the above information, this variant is considered pathogenic. REFERENCES Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010 May;1802(5):478-84. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81. Schiff M et al. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013 May;109(1):21-7.

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

Last Updated: Apr 17, 2019

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