NM_000018.4(ACADVL):c.1591C>T (p.Arg531Trp) AND Very long chain acyl-CoA dehydrogenase deficiency

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(3);Uncertain significance(2) (Last evaluated: Nov 2, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
6 submissions [Details]
Record status:
current
Accession:
RCV000652029.8

Allele description [Variation Report for NM_000018.4(ACADVL):c.1591C>T (p.Arg531Trp)]

NM_000018.4(ACADVL):c.1591C>T (p.Arg531Trp)

Gene:
ACADVL:acyl-CoA dehydrogenase very long chain [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17p13.1
Genomic location:
Preferred name:
NM_000018.4(ACADVL):c.1591C>T (p.Arg531Trp)
HGVS:
  • NC_000017.11:g.7224379C>T
  • NG_007975.1:g.9546C>T
  • NG_008391.2:g.672G>A
  • NG_033038.1:g.15166G>A
  • NM_000018.4:c.1591C>TMANE SELECT
  • NM_001033859.3:c.1525C>T
  • NM_001270447.2:c.1660C>T
  • NM_001270448.1:c.1363C>T
  • NM_001270448.2:c.1363C>T
  • NP_000009.1:p.Arg531Trp
  • NP_000009.1:p.Arg531Trp
  • NP_001029031.1:p.Arg509Trp
  • NP_001257376.1:p.Arg554Trp
  • NP_001257377.1:p.Arg455Trp
  • NP_001257377.1:p.Arg455Trp
  • NC_000017.10:g.7127698C>T
  • NM_000018.3:c.1591C>T
Protein change:
R455W
Links:
dbSNP: rs146379816
NCBI 1000 Genomes Browser:
rs146379816
Molecular consequence:
  • NM_000018.4:c.1591C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001033859.3:c.1525C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270447.2:c.1660C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270448.1:c.1363C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270448.2:c.1363C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000773889Invitaecriteria provided, single submitter
Likely pathogenic
(Nov 2, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000791958Counsylcriteria provided, single submitter
Uncertain significance
(Jun 5, 2017)
unknownclinical testing

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

Citation Link,

SCV000914788Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Aug 9, 2018)
germlineclinical testing

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

Citation Link,

SCV001163426Baylor Geneticscriteria provided, single submitter
Likely pathogenicgermlineclinical testing

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

SCV001365228Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicinecriteria provided, single submitter
Likely pathogenic
(Nov 1, 2019)
germlineclinical testing

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

SCV001459259Natera, Inc.no assertion criteria providedUncertain significance
(Sep 16, 2020)
germlineclinical testing

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

Clinical and biochemical outcome of patients with very long-chain acyl-CoA dehydrogenase deficiency.

Rovelli V, Manzoni F, Viau K, Pasquali M, Longo N.

Mol Genet Metab. 2019 May;127(1):64-73. doi: 10.1016/j.ymgme.2019.04.001. Epub 2019 Apr 16.

PubMed [citation]
PMID:
31031081

Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database.

Pena LD, van Calcar SC, Hansen J, Edick MJ, Walsh Vockley C, Leslie N, Cameron C, Mohsen AW, Berry SA, Arnold GL, Vockley J; IBEMC..

Mol Genet Metab. 2016 Aug;118(4):272-81. doi: 10.1016/j.ymgme.2016.05.007. Epub 2016 May 13.

PubMed [citation]
PMID:
27209629
PMCID:
PMC4970910
See all PubMed Citations (8)

Details of each submission

From Invitae, SCV000773889.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces arginine with tryptophan at codon 531 of the ACADVL protein (p.Arg531Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs146379816, ExAC 0.08%). This variant has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 21932095, 31031081). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Arg491Trp in the literature. ClinVar contains an entry for this variant (Variation ID: 166647). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). This variant disrupts the p.Arg531 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been observed in individuals with ACADVL-related conditions (PMID: 27209629), which suggests that this may be a clinically significant amino acid residue. 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 Counsyl, SCV000791958.1

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

From Illumina Clinical Services Laboratory,Illumina, SCV000914788.1

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

Description

The ACADVL c.1591C>T (p.Arg531Trp) variant is a missense variant that has been reported in a compound heterozygous state with a canonical splice site variant in one individual with VLCAD deficiency who had residual enzyme activity of 21% (Hoffman et al. 2017). It has also been identified in a heterozygous state in four individuals with suspected VLCAD deficiency in whom a second variant was not identified (Miller et al. 2015; Ghosh et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000806 in the European (non-Finnish) population of the the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Arg531Trp variant is therefore classified as a variant of uncertain significance but suspicious for pathogenicity for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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

From Baylor Genetics, SCV001163426.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#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, SCV001365228.2

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

Description

The NM_000018.3:c.1591C>T (NP_000009.1:p.Arg531Trp) [GRCH38: NC_000017.11:g.7224379C>T] variant in ACADVL gene is interpretated to be Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PS3, PM3, PP3, PP4

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

From Natera, Inc., SCV001459259.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

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