NM_000018.4(ACADVL):c.887_888del (p.Pro296fs) AND Very long chain acyl-CoA dehydrogenase deficiency

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: May 21, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000169392.5

Allele description [Variation Report for NM_000018.4(ACADVL):c.887_888del (p.Pro296fs)]

NM_000018.4(ACADVL):c.887_888del (p.Pro296fs)

Gene:
ACADVL:acyl-CoA dehydrogenase very long chain [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
17p13.1
Genomic location:
Preferred name:
NM_000018.4(ACADVL):c.887_888del (p.Pro296fs)
HGVS:
  • NC_000017.11:g.7222675_7222676del
  • NG_007975.1:g.7842_7843del
  • NG_008391.2:g.2375_2376del
  • NM_000018.4:c.887_888delMANE SELECT
  • NM_001033859.2:c.821_822del
  • NM_001270447.1:c.956_957del
  • NM_001270448.1:c.659_660del
  • NP_000009.1:p.Pro296fs
  • NP_001029031.1:p.Pro274fs
  • NP_001257376.1:p.Pro319fs
  • NP_001257377.1:p.Pro220fs
  • NC_000017.10:g.7125994_7125995del
  • NM_000018.2:c.887_888delCT
  • NM_000018.3:c.887_888del
  • NM_000018.3:c.887_888delCT
  • p.P296RfsX17
Protein change:
P220fs
Links:
dbSNP: rs753108198
NCBI 1000 Genomes Browser:
rs753108198
Molecular consequence:
  • NM_000018.4:c.887_888del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001033859.2:c.821_822del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001270447.1:c.956_957del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001270448.1:c.659_660del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000220784Counsylcriteria provided, single submitter
Likely pathogenic
(Oct 10, 2014)
unknownliterature only

PubMed (3)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000693968Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Nov 1, 2019)
germlineclinical testing

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

Citation Link,

SCV001201176Invitaecriteria provided, single submitter
Pathogenic
(May 21, 2020)
germlineclinical testing

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

SCV001364908Wong 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]

Summary from all submissions

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

Citations

PubMed

Treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an anaplerotic odd-chain triglyceride.

Roe CR, Sweetman L, Roe DS, David F, Brunengraber H.

J Clin Invest. 2002 Jul;110(2):259-69.

PubMed [citation]
PMID:
12122118
PMCID:
PMC151060

Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States.

Miller MJ, Burrage LC, Gibson JB, Strenk ME, Lose EJ, Bick DP, Elsea SH, Sutton VR, Sun Q, Graham BH, Craigen WJ, Zhang VW, Wong LJ.

Mol Genet Metab. 2015 Nov;116(3):139-45. doi: 10.1016/j.ymgme.2015.08.011. Epub 2015 Sep 2.

PubMed [citation]
PMID:
26385305
PMCID:
PMC4790081
See all PubMed Citations (10)

Details of each submission

From Counsyl, SCV000220784.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000693968.2

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

Description

Variant summary: ACADVL c.887_888delCT (p.Pro296ArgfsX17) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250254 control chromosomes (gnomAD). c.887_888delCT has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Hesse_2018, Mathur_1999, Schiff_2013, Wang_2019). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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

From Invitae, SCV001201176.2

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

Description

This sequence change creates a premature translational stop signal (p.Pro296Argfs*17) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs753108198, ExAC 0.01%). This variant has been observed in combination with another ACADVL variant in individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 23480858, 30194637). ClinVar contains an entry for this variant (Variation ID: 189008). 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, SCV001364908.2

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

Description

The NM_000018.3:c.887_888delCT (NP_000009.1:p.Pro296ArgfsTer17) [GRCH38: NC_000017.11:g.7222675_7222676delCT] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 10077518. 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

Last Updated: Jun 14, 2021

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