NM_000018.4(ACADVL):c.105_109dup (p.Arg37fs) AND Very long chain acyl-CoA dehydrogenase deficiency

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Pathogenic(1);Uncertain significance(1) (Last evaluated: Nov 1, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000665413.3

Allele description [Variation Report for NM_000018.4(ACADVL):c.105_109dup (p.Arg37fs)]

NM_000018.4(ACADVL):c.105_109dup (p.Arg37fs)

Gene:
ACADVL:acyl-CoA dehydrogenase very long chain [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
17p13.1
Genomic location:
Preferred name:
NM_000018.4(ACADVL):c.105_109dup (p.Arg37fs)
HGVS:
  • NC_000017.11:g.7220164_7220168dup
  • NG_007975.1:g.5331_5335dup
  • NG_008391.2:g.4887_4891dup
  • NM_000018.4:c.105_109dupMANE SELECT
  • NM_001033859.2:c.105_109dup
  • NM_001270447.1:c.174_178dup
  • NM_001270448.1:c.-124_-120dup
  • NP_000009.1:p.Arg37fs
  • NP_001029031.1:p.Arg37fs
  • NP_001257376.1:p.Arg60fs
  • NC_000017.10:g.7123483_7123487dup
  • NM_000018.3:c.105_109dupTGCCC
Protein change:
R37fs
Links:
dbSNP: rs1555527532
NCBI 1000 Genomes Browser:
rs1555527532
Molecular consequence:
  • NM_001270448.1:c.-124_-120dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000018.4:c.105_109dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001033859.2:c.105_109dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001270447.1:c.174_178dup - 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
SCV000789532Counsylcriteria provided, single submitter
Likely pathogenic
(Feb 8, 2017)
unknownclinical testing

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

Citation Link,

SCV000914787Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Nov 21, 2018)
germlineclinical testing

Citation Link,

SCV001364947Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicinecriteria provided, single submitter
Pathogenic
(Nov 1, 2019)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Counsyl, SCV000789532.1

#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 Illumina Clinical Services Laboratory,Illumina, SCV000914787.1

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

Description

The ACADVL c.100_101insGCCCT (p.Arg37LeufsTer26) variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease.

#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, SCV001364947.2

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

Description

The NM_000018.3:c.105_109dupTGCCC (NP_000009.1:p.Arg37LeufsTer26) [GRCH38: NC_000017.11:g.7220164_7220168dupTGCCC] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. 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: Apr 12, 2021

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