NM_000018.4(ACADVL):c.1019G>T (p.Gly340Val) AND not provided

Clinical significance:Likely pathogenic (Last evaluated: Jul 27, 2017)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000489813.1

Allele description [Variation Report for NM_000018.4(ACADVL):c.1019G>T (p.Gly340Val)]

NM_000018.4(ACADVL):c.1019G>T (p.Gly340Val)

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.1019G>T (p.Gly340Val)
HGVS:
  • NC_000017.11:g.7222807G>T
  • NG_007975.1:g.7974G>T
  • NM_000018.4:c.1019G>T
  • NM_001270448.1:c.791G>T
  • NP_000009.1:p.Gly340Val
  • NP_001257377.1:p.Gly264Val
  • NC_000017.10:g.7126126G>T
  • NM_000018.2:c.1019G>T
  • NM_000018.3:c.1019G>T
Protein change:
G264V
Links:
dbSNP: rs934797393
NCBI 1000 Genomes Browser:
rs934797393
Molecular consequence:
  • NM_000018.3:c.1019G>T - 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
SCV000576556GeneDxcriteria provided, single submitter
Likely pathogenic
(Apr 27, 2017)
germlineclinical testing

Citation Link,

SCV000884953ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Likely pathogenic
(Jul 27, 2017)
germlineclinical testing

Citation Link

Summary from all submissions

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

Details of each submission

From GeneDx, SCV000576556.3

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

Description

The G340V variant has been reported in multiple patients with abnormal newborn screening results for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency in whom a second variant was not identified in the ACADVL gene (Miller et al. 2015). The G340V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G340V variant is a conservative amino acid substitution that occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A different missense variant at the same position (G340E) has also been reported in the Human Gene Mutation Database in association with VLCAD deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we interpret G340V as likely pathogenic.

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

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV000884953.1

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

Description

The ACADVL c.1019G>T;p.Gly340Val variant has been described in the medical literature in individuals identified by newborn screen and at least one reportedly symptomatic adult (Evans 2016, Miller 2015, Olpin 2017). The variant is listed in the ClinVar database (Variation ID: 426177) but not the dbSNP variant database or the general population-based databases (Exome Variant Server, Genome Aggregation Database). The amino acid at this position is well conserved across species, located near the active site (McAndrew 2008), and computational algorithms (AlignGVGD, PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is considered likely pathogenic. References: Evans M et al. VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria. Mol Genet Metab. 2016 Aug;118(4):282-7. McAndrew RP et al. Structural basis for substrate fatty acyl chain specificity: crystal structure of human very-long-chain acyl-CoA dehydrogenase. J Biol Chem. 2008 Apr 4;283(14):9435-43. Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. Olpin SE et al. Fibroblast Fatty-Acid Oxidation Flux Assays Stratify Risk in Newborns with Presumptive-Positive Results on Screening for Very-Long Chain Acyl-CoA Dehydrogenase Deficiency. Int J Neonat Screen. 2017 3(1):2.

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

Last Updated: Apr 17, 2019

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