NM_000018.4(ACADVL):c.865G>A (p.Gly289Arg) AND Very long chain acyl-CoA dehydrogenase deficiency

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 16, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
6 submissions [Details]
Record status:
current
Accession:
RCV000408960.11

Allele description [Variation Report for NM_000018.4(ACADVL):c.865G>A (p.Gly289Arg)]

NM_000018.4(ACADVL):c.865G>A (p.Gly289Arg)

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.865G>A (p.Gly289Arg)
HGVS:
  • NC_000017.11:g.7222289G>A
  • NG_007975.1:g.7456G>A
  • NG_008391.2:g.2762C>T
  • NM_000018.4:c.865G>AMANE SELECT
  • NM_001033859.2:c.799G>A
  • NM_001270447.1:c.934G>A
  • NM_001270448.1:c.637G>A
  • NP_000009.1:p.Gly289Arg
  • NP_001029031.1:p.Gly267Arg
  • NP_001257376.1:p.Gly312Arg
  • NP_001257377.1:p.Gly213Arg
  • NC_000017.10:g.7125608G>A
  • NM_000018.2:c.865G>A
  • NM_000018.3:c.865G>A
Protein change:
G213R
Links:
dbSNP: rs200788251
NCBI 1000 Genomes Browser:
rs200788251
Molecular consequence:
  • NM_000018.4:c.865G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001033859.2:c.799G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270447.1:c.934G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270448.1:c.637G>A - 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
SCV000486424Counsylno assertion criteria providedLikely pathogenic
(May 27, 2016)
unknownclinical testing

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

SCV000820769Invitaecriteria provided, single submitter
Pathogenic
(Oct 16, 2020)
germlineclinical testing

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

SCV000915776Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Pathogenic
(Jan 22, 2018)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV001156589ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Likely pathogenic
(Nov 3, 2019)
germlineclinical testing

Citation Link,

SCV001163425Baylor Geneticscriteria provided, single submitter
Pathogenicgermlineclinical testing

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

SCV001364906Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicinecriteria provided, single submitter
Pathogenic
(Nov 1, 2019)
germlineclinical testing

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

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

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

Neuropsychological outcomes in fatty acid oxidation disorders: 85 cases detected by newborn screening.

Waisbren SE, Landau Y, Wilson J, Vockley J.

Dev Disabil Res Rev. 2013;17(3):260-8. doi: 10.1002/ddrr.1119.

PubMed [citation]
PMID:
23798014
PMCID:
PMC4137760
See all PubMed Citations (8)

Details of each submission

From Counsyl, SCV000486424.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000820769.4

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

Description

This sequence change replaces glycine with arginine at codon 289 of the ACADVL protein (p.Gly289Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs200788251, ExAC 0.02%). This variant has been reported in combination with another ACADVL variant in individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 27246109, 27209629, 14517516, 23480858). This variant is also known in the literature as Gly249Arg. ClinVar contains an entry for this variant (Variation ID: 370981). Experimental studies have shown that this missense change causes a large reduction in ACADVL enzyme activity (PMID: 23480858). For these reasons, this variant has been classified as Pathogenic.

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

From Illumina Clinical Services Laboratory,Illumina, SCV000915776.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Across a selection of the available literature, the ACADVL c.865G>A (p.Gly289Arg) variant has been reported in a compound heterozygous state in at least six individuals identified as having VLCAD deficiency through newborn screening (Spiekerkoetter et al. 2003; Schiff et al. 2013; Waisbren et al. 2013; Pena et al. 2016; Evans et al. 2016). Several of these individuals were described as asymptomatic, however, speech/language and motor delays, autistic spectrum behavior and relative weakness in the fine motor area were reported in two individuals after at least two years of follow-up (Waisbren et al. 2013). Analysis of 693 unrelated individuals with a positive newborn screening result for VLCAD deficiency, identified the p.Gly289Arg variant on six alleles from affected individuals (Miller et al. (2015). Control data are unavailable for this variant, which is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Fibroblasts from one individual who was compound heterozygous for the p.Gly289Arg variant, exhibited no detectable enzyme activity and absent protein expression based on Western blot analysis. In vitro expression analyses in E. coli showed that the p.Gly289Arg variant displayed 15% of wildtype activity and reduced protein expression (Schiff et al. 2013). Based on the collective evidence, the p.Gly289Arg variant is classified as pathogenic 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 ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001156589.2

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

Description

The ACADVL c.865G>A; p.Gly289Arg variant (rs200788251), also known as p.Gly249Arg, is reported in the literature in the compound heterozygous state in individuals affected with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Evans 2016, Pena 2016, Schiff 2013, Spiekerkoetter 2003). This variant is also reported in ClinVar (Variation ID: 370981). It is found in the general population with an overall allele frequency of 0.01% (32/282608 alleles) in the Genome Aggregation Database. The glycine at codon 289 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Furthermore, in vitro functional analyses demonstrate a significant reduction in protein activity compared to wildtype (Schiff 2013). Based on available information, this variant is considered to be likely pathogenic. REFERENCES Evans M et al. VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria. Mol Genet Metab. 2016 Aug;118(4):282-7. 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. Schiff M et al. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013 109(1):21-7. Spiekerkoetter U et al. MS/MS-based newborn and family screening detects asymptomatic patients with very-long-chain acyl-CoA dehydrogenase deficiency. J Pediatr. 2003 143(3):335-42.

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

From Baylor Genetics, SCV001163425.1

#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, SCV001364906.2

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

Description

The NM_000018.3:c.865G>A (NP_000009.1:p.Gly289Arg) [GRCH38: NC_000017.11:g.7222289G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 14517516; 27209629 . This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3

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

Last Updated: May 10, 2021

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