NM_000018.2(ACADVL):c.343delG (p.Glu115Lysfs) AND Very long chain acyl-CoA dehydrogenase deficiency

Clinical significance:Pathogenic (Last evaluated: Oct 16, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000001691.18

Allele description [Variation Report for NM_000018.2(ACADVL):c.343delG (p.Glu115Lysfs)]

NM_000018.2(ACADVL):c.343delG (p.Glu115Lysfs)

Gene:
ACADVL:acyl-CoA dehydrogenase very long chain [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
17p13.1
Genomic location:
Preferred name:
NM_000018.2(ACADVL):c.343delG (p.Glu115Lysfs)
Other names:
ACADVL, 135-BP DEL
HGVS:
  • NC_000017.11:g.7220924del
  • NG_007975.1:g.6091del
  • NG_008391.2:g.4128del
  • XR_934023.2:n.402del
  • NC_000017.10:g.7124242del
  • NC_000017.10:g.7124243del
  • NM_000018.2:c.343delG
  • NM_000018.3:c.343del
  • NM_000018.3:c.343delG
Links:
OMIM: 609575.0004; OMIM: 609575.0005; dbSNP: rs387906249
NCBI 1000 Genomes Browser:
rs387906249
Functional consequence:
exon loss [PubMedVariation Ontology: 0381]

Condition(s)

Name:
Very long chain acyl-CoA dehydrogenase deficiency (VLCAD)
Synonyms:
VLCAD deficiency
Identifiers:
MONDO: MONDO:0008723; MedGen: C3887523; Orphanet: 26793; OMIM: 201475

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000021847OMIMno assertion criteria providedPathogenic
(Nov 7, 1995)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV000220752Counsylno assertion criteria providedLikely pathogenic
(Oct 9, 2015)
unknownclinical testing

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

SCV000773901Invitaecriteria provided, single submitter
Pathogenic
(Oct 16, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001364886Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicinecriteria provided, single submitter
Pathogenic
(Nov 1, 2019)
germlineclinical testing

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

SCV001372383Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jun 20, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedunknownunknownnot 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

Gestational, pathologic and biochemical differences between very long-chain acyl-CoA dehydrogenase deficiency and long-chain acyl-CoA dehydrogenase deficiency in the mouse.

Cox KB, Hamm DA, Millington DS, Matern D, Vockley J, Rinaldo P, Pinkert CA, Rhead WJ, Lindsey JR, Wood PA.

Hum Mol Genet. 2001 Sep 15;10(19):2069-77.

PubMed [citation]
PMID:
11590124
See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000021847.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In a patient with VLCAD deficiency (201475) associated with infantile cardiomyopathy and sudden death, Strauss et al. (1995) identified compound heterozygosity for 2 mutations in the ACADVL gene: R613W (609575.0003) and a 1-bp deletion of one of the 2 guanine nucleotides forming the intron-exon 6 boundary. The normal sequence is ccccagGAA and the mutant sequence was cccaGAA. The authors noted that the most likely consequence of this deletion would be an alternation in splicing because of loss of the conserved ag dinucleotide at the splice acceptor site. Alternatively, splicing at this site might occur but this would result in loss of a single nucleotide in exon 6, causing a shift in the mRNA reading frame. In either event, this mutation would most likely result in an unstable mRNA and lack of VLCAD protein expression from the mutant allele.

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

From Counsyl, SCV000220752.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000773901.5

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

Description

This sequence change creates a premature translational stop signal (p.Glu115Lysfs*2) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs387906250, ExAC 0.002%). This variant has been reported in combination with another ACADVL variant in two individuals affected with very long chain acyl-CoA dehydrogenase (PMID: 27246109, 23867825). ClinVar contains an entry for this variant (Variation ID: 1624). Loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). For these reasons, this variant has been classified as Pathogenic.

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

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001364886.2

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

Description

The NM_000018.3:c.343delG (NP_000009.1:p.Glu115LysfsTer2) [GRCH38: NC_000017.11:g.7220924delG] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 7479827. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001372383.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Variant summary: ACADVL c.343delG (p.Glu115LysfsX2 also referred to as c.343-1delG) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant also deletes a conserved exonic nucleotide located adjacent to intron 5 splice acceptor site of the ACADVL gene: 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 277170 control chromosomes (gnomAD). c.343delG has been reported in the literature in multiple compound heterozygous individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency ( example, Strauss 1995, Mathur 1999, Evans 2016, Gillingham 2017, Ndukwe Erlingsson 2013, Olpin 2017). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function (example, Hesse 2018, Mathur 1999, Strauss 1995). The most pronounced variant effect results in <10% of normal activity in cell lines bearing this variant as a compound heterozygous genotype, while the variant results in 32% of normal activity in heterozygous patient fibroblasts. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Jun 14, 2021

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