NM_000018.4(ACADVL):c.889_891del (p.Glu297del) AND Very long chain acyl-CoA dehydrogenase deficiency

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(2) (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:
RCV001061118.4

Allele description [Variation Report for NM_000018.4(ACADVL):c.889_891del (p.Glu297del)]

NM_000018.4(ACADVL):c.889_891del (p.Glu297del)

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.889_891del (p.Glu297del)
HGVS:
  • NC_000017.11:g.7222677_7222679del
  • NG_007975.1:g.7844_7846del
  • NG_008391.2:g.2372_2374del
  • NM_000018.4:c.889_891delMANE SELECT
  • NM_001033859.2:c.823_825del
  • NM_001270447.1:c.958_960del
  • NM_001270448.1:c.661_663del
  • NP_000009.1:p.Glu297del
  • NP_001029031.1:p.Glu275del
  • NP_001257376.1:p.Glu320del
  • NP_001257377.1:p.Glu221del
  • NC_000017.10:g.7125996_7125998del
  • NC_000017.10:g.7125996_7125998delGAG
  • NM_000018.2:c.889_891delGAG
  • NM_000018.3:c.889_891del
  • NM_000018.3:c.889_891delGAG
  • p.E297del
Protein change:
E221del
Links:
dbSNP: rs796051914
NCBI 1000 Genomes Browser:
rs796051914
Molecular consequence:
  • NM_000018.4:c.889_891del - inframe_deletion - [Sequence Ontology: SO:0001822]
  • NM_001033859.2:c.823_825del - inframe_deletion - [Sequence Ontology: SO:0001822]
  • NM_001270447.1:c.958_960del - inframe_deletion - [Sequence Ontology: SO:0001822]
  • NM_001270448.1:c.661_663del - inframe_deletion - [Sequence Ontology: SO:0001822]

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
SCV001225850Invitaecriteria provided, single submitter
Uncertain significance
(Jun 16, 2019)
germlineclinical testing

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

SCV001365053Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicinecriteria provided, single submitter
Uncertain significance
(Nov 1, 2019)
germlineclinical testing

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

SCV001474560ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Sep 17, 2019)
germlineclinical testing

Citation Link

Summary from all submissions

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

Citations

PubMed

Neurodevelopmental profiles of children with very long chain acyl-CoA dehydrogenase deficiency diagnosed by newborn screening.

Brown A, Crowe L, Andresen BS, Anderson V, Boneh A.

Mol Genet Metab. 2014 Dec;113(4):278-82. doi: 10.1016/j.ymgme.2014.10.005. Epub 2014 Oct 12.

PubMed [citation]
PMID:
25456746

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 (4)

Details of each submission

From Invitae, SCV001225850.2

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

Description

This variant, c.889_891del, results in the deletion of 1 amino acid(s) of the ACADVL protein (p.Glu297del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with VLCAD (PMID: 25456746) and in several individuals with abnormal newborn screening results suggestive of VLCAD (PMID: 26385305). ClinVar contains an entry for this variant (Variation ID: 203590). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#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, SCV001365053.2

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

Description

The NM_000018.3:c.889_891delGAG (NP_000009.1:p.Glu297del) [GRCH38: NC_000017.11:g.7222677_7222679del] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PP3

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

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001474560.1

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

Description

The ACADVL c.889_891delGAG; p.Glu297del variant (rs796051914), also known as Glu257del, deletes three nucleotides resulting in an in-frame deletion of a single glutamate residue. This variant has been reported in a patient with a confirmed diagnosis of VLCAD deficiency who was also heterozygous for another ACADVL variant (Brown 2014), and is reported as a recurrent variant in positive newborn screening for VLCAD deficiency (Miller 2015). Additionally, our lab has identified this variant in several heterozygous carriers, and in an individual who carried an additional pathogenic ACADVL variant. Furthermore, other single amino acid deletions (Glu130del, Glu277del, Lys299del) have been reported in association with VLCAD deficiency (Miller 2015, Pena 2016). The p.Glu297del variant is reported in ClinVar (Variation ID: 203590), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). Based on the above information, this variant is considered pathogenic. REFERENCES Brown A et al. Neurodevelopmental profiles of children with very long chain acyl-CoA dehydrogenase deficiency diagnosed by newborn screening. Mol Genet Metab. 2014 Dec;113(4):278-82. 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. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81.

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

Last Updated: Apr 12, 2021

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