NM_000018.4(ACADVL):c.1077_1077+1delinsCAC AND Very long chain acyl-CoA dehydrogenase deficiency

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Nov 1, 2019)

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:
RCV000411230.5

Allele description [Variation Report for NM_000018.4(ACADVL):c.1077_1077+1delinsCAC]

NM_000018.4(ACADVL):c.1077_1077+1delinsCAC

Gene:
ACADVL:acyl-CoA dehydrogenase very long chain [Gene - OMIM - HGNC]
Variant type:
Indel
Cytogenetic location:
17p13.1
Genomic location:
Preferred name:
NM_000018.4(ACADVL):c.1077_1077+1delinsCAC
HGVS:
  • NC_000017.11:g.7222865_7222866delinsCAC
  • NG_007975.1:g.8032_8033delinsCAC
  • NG_008391.2:g.2185_2186delinsGTG
  • NM_000018.4:c.1077_1077+1delinsCACMANE SELECT
  • NM_001033859.2:c.1011_1011+1delinsCAC
  • NM_001270447.1:c.1146_1146+1delinsCAC
  • NM_001270448.1:c.849_849+1delinsCAC
  • NC_000017.10:g.7126184_7126185delinsCAC
  • NM_000018.2:c.1077_1077+1delinsCAC
  • NM_000018.3:c.1077_1077+1delGGinsCAC
Links:
dbSNP: rs1057516686
NCBI 1000 Genomes Browser:
rs1057516686
Molecular consequence:
  • NM_000018.4:c.1077_1077+1delinsCAC - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001033859.2:c.1011_1011+1delinsCAC - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001270447.1:c.1146_1146+1delinsCAC - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001270448.1:c.849_849+1delinsCAC - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000486065Counsylcriteria provided, single submitter
Likely pathogenic
(Mar 23, 2016)
unknownclinical testing

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

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

SCV000773894Invitaecriteria provided, single submitter
Likely pathogenic
(Jun 24, 2019)
germlineclinical testing

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

SCV000916405Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Oct 22, 2018)
germlineclinical testing

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

Citation Link,

SCV001364912Wong 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 providedclinical testing

Citations

PubMed

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000486065.1

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

From Invitae, SCV000773894.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change affects a donor splice site in intron 10 of the ACADVL gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in whom no second allele was reported and who was affected with very long chain acyl-CoA dehydrogenase deficiency (PMID: 9973285). ClinVar contains an entry for this variant (Variation ID: 370686). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000916405.1

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

Description

Variant summary: ACADVL c.1077_1077+1delinsCAC is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 244794 control chromosomes (gnomAD). The variant, c.1077_1077+1delinsCAC, has been reported in the literature in one individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency in whom no second allele was reported so the exact genotype could not be inferred (Andresen_1999). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely 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, SCV001364912.2

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

Description

The NM_000018.3:c.1077_1077+1delinsCAC (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7222865_7222866delinsCAC] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:9973285. 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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