NM_000018.4(ACADVL):c.1096C>T (p.Arg366Cys) AND Very long chain acyl-CoA dehydrogenase deficiency

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(3);Uncertain significance(1) (Last evaluated: Nov 1, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000675110.7

Allele description [Variation Report for NM_000018.4(ACADVL):c.1096C>T (p.Arg366Cys)]

NM_000018.4(ACADVL):c.1096C>T (p.Arg366Cys)

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.1096C>T (p.Arg366Cys)
Other names:
p.R366C:CGT>TGT
HGVS:
  • NC_000017.11:g.7223151C>T
  • NG_007975.1:g.8318C>T
  • NG_008391.2:g.1900G>A
  • NM_000018.4:c.1096C>TMANE SELECT
  • NM_001033859.2:c.1030C>T
  • NM_001270447.1:c.1165C>T
  • NM_001270448.1:c.868C>T
  • NP_000009.1:p.Arg366Cys
  • NP_001029031.1:p.Arg344Cys
  • NP_001257376.1:p.Arg389Cys
  • NP_001257377.1:p.Arg290Cys
  • NC_000017.10:g.7126470C>T
  • NM_000018.2:c.1096C>T
  • NM_000018.3:c.1096C>T
  • NM_001033859.1:c.1030C>T
  • P49748:p.Arg366Cys
Protein change:
R290C
Links:
UniProtKB: P49748#VAR_000349; dbSNP: rs771874163
NCBI 1000 Genomes Browser:
rs771874163
Molecular consequence:
  • NM_000018.4:c.1096C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001033859.2:c.1030C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270447.1:c.1165C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270448.1:c.868C>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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000602375ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Sep 20, 2019)
germlineclinical testing

Citation Link,

SCV000800658Counsylcriteria provided, single submitter
Uncertain significance
(Jan 30, 2018)
unknownclinical testing

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

Citation Link,

SCV000832501Invitaecriteria provided, single submitter
Pathogenic
(Nov 1, 2020)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV001364914Wong 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]

SCV001455138Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

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

VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment.

Hoffmann L, Haussmann U, Mueller M, Spiekerkoetter U.

J Inherit Metab Dis. 2012 Mar;35(2):269-77. doi: 10.1007/s10545-011-9391-8. Epub 2011 Sep 20.

PubMed [citation]
PMID:
21932095
See all PubMed Citations (10)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV000602375.2

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

Description

The ACADVL c.1096C>T; p.Arg366Cys variant (rs771874163), also known as p.Arg326Cys, is reported in the literature in individuals affected with VLCAD deficiency (Andresen 1996, Andresen 1999, Hoffman 2012). Analysis of enzymatic palmitoyl-CoA dehydrogenase activity in affected individuals indicates that the variant protein has reduced activity compared to wildtype, with individuals showing residual activity less than 50 percent in fibroblasts (Andresen 1996) or lymphocytes (Hoffman 2012, Spiekerkoetter 2010). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 203579) and is found in the general population with an overall allele frequency of 0.002% (5/246272 alleles) in the Genome Aggregation Database. An additional variant at this codon (c.1097G>A, p.Arg366His) has been reported in individuals with VLCAD deficiency and is considered pathogenic (Andresen 1999, Gobin-Limballe 2010). The arginine at codon 366 is highly conserved and forms a salt bridge with the FAD cofactor in the neighboring subunit of an ACADVL dimer, thus promoting both FAD binding and association of enzyme monomers (Gobin-Limballe 2010, Hoffman 2012, McAndrew 2008). Computational analyses (SIFT, PolyPhen-2) further predict that the p.Arg366Cys variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Andresen BS et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999 Feb;64(2):479-94. Andresen BS et al. Cloning and characterization of human very-long-chain acyl-CoA dehydrogenase cDNA, chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene. Hum Mol Genet. 1996 Apr;5(4):461-72. Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010 May;1802(5):478-84. Hoffmann L et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012 Mar;35(2):269-77. McAndrew RP et al. Structural basis for substrate fatty acyl chain specificity: crystal structure of human very-long-chain acyl-CoA dehydrogenase. J Biol Chem. 2008 Apr 4;283(14):9435-43. Spiekerkoetter U et al. Tandem mass spectrometry screening for very long-chain acyl-CoA dehydrogenase deficiency: the value of second-tier enzyme testing. J Pediatr. 2010 Oct;157(4):668-73.

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

From Counsyl, SCV000800658.1

#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 Invitae, SCV000832501.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change replaces arginine with cysteine at codon 366 of the ACADVL protein (p.Arg366Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs771874163, ExAC 0.02%). This variant has been reported in combination with two other ACADVL variants in an individual affected with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 8845838, Invitae) and in affected individuals in whom no second allele was reported (PMID: 21932095, 9973285). In one of these individuals the variant was observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with this condition. This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as p.Arg326Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 203579). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Arg366His) has been determined to be pathogenic (PMID: 24263034, 16488171, 20060901, 27246109) and is also known as p.Arg326His in the literature. This suggests that the arginine residue is critical for ACADVL protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as 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, SCV001364914.2

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

Description

The NM_000018.3:c.1096C>T (NP_000009.1:p.Arg366Cys) [GRCH38: NC_000017.11:g.7223151C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 8845838. 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

From Natera, Inc., SCV001455138.1

#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: May 10, 2021

Support Center