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NM_000018.4(ACADVL):c.1097G>A (p.Arg366His) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:
Likely pathogenic (9 submissions)
Last evaluated:
Sep 22, 2022
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000411732.26

Allele description

NM_000018.4(ACADVL):c.1097G>A (p.Arg366His)

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.1097G>A (p.Arg366His)
Other names:
p.R366H:CGT>CAT; NM_000018.4(ACADVL):c.1097G>A
HGVS:
  • NC_000017.11:g.7223152G>A
  • NG_007975.1:g.8319G>A
  • NG_008391.2:g.1899C>T
  • NM_000018.4:c.1097G>AMANE SELECT
  • NM_001033859.3:c.1031G>A
  • NM_001270447.2:c.1166G>A
  • NM_001270448.2:c.869G>A
  • NP_000009.1:p.Arg366His
  • NP_001029031.1:p.Arg344His
  • NP_001257376.1:p.Arg389His
  • NP_001257376.1:p.Arg389His
  • NP_001257377.1:p.Arg290His
  • NP_001257377.1:p.Arg290His
  • NC_000017.10:g.7126471G>A
  • NM_000018.2:c.1097G>A
  • NM_000018.3:c.1097G>A
  • NM_001270447.1:c.1166G>A
  • NM_001270448.1:c.869G>A
  • P49748:p.Arg366His
Protein change:
R290H
Links:
UniProtKB: P49748#VAR_000350; dbSNP: rs112406105
NCBI 1000 Genomes Browser:
rs112406105
Molecular consequence:
  • NM_000018.4:c.1097G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001033859.3:c.1031G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270447.2:c.1166G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270448.2:c.869G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Very long chain acyl-CoA dehydrogenase deficiency (ACADVLD)
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
SCV000486429Counsyl
criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))
Likely pathogenic
(May 27, 2016)
unknownclinical testing

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

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

SCV000836322Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 28, 2024)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV000883344ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)
Pathogenic
(Jan 25, 2022)
germlineclinical testing

Citation Link,

SCV000915777Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)
Pathogenic
(Jan 9, 2019)
germlineclinical testing

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

Citation Link,

SCV001364915Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Nov 1, 2019)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001443688Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenicgermlineclinical testing

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

SCV001455139Natera, Inc.
no assertion criteria provided
Pathogenic
(Sep 16, 2020)
germlineclinical testing

SCV002576746ClinGen ACADVL Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(clingen acadvl acmg specifications v1)
Likely pathogenic
(Sep 22, 2022)
germlinecuration

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV004214062Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 30, 2024)
unknownclinical 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 providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

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

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.

Andresen BS, Bross P, Vianey-Saban C, Divry P, Zabot MT, Roe CR, Nada MA, Byskov A, Kruse TA, Neve S, Kristiansen K, Knudsen I, Corydon MJ, Gregersen N.

Hum Mol Genet. 1996 Apr;5(4):461-72. Erratum in: Hum Mol Genet 1996 Sep;5(9):1390.

PubMed [citation]
PMID:
8845838
See all PubMed Citations (11)

Details of each submission

From Counsyl, SCV000486429.2

#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 Invitae, SCV000836322.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 366 of the ACADVL protein (p.Arg366His). This variant is present in population databases (rs112406105, gnomAD 0.01%). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 20060901, 24263034, 27246109). This variant is also known as p.Arg326His. ClinVar contains an entry for this variant (Variation ID: 203580). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function with a positive predictive value of 95%. This variant disrupts the p.Arg366 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8845838, 9973285, 21932095; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000883344.4

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

Description

The ACADVL c.1097G>A; p.Arg366His variant (rs112406105), also known as Arg326His, has been reported in individuals with VLCAD deficiency both in the homozygous state and as compound heterozygous with another ACADVL pathogenic variant (Andresen 1999, Antunes 2013, Evans 2016, Gobin-Limballe 2010). Additionally, a different alteration at this codon (p.Arg366Cys) has also been associated with VLCAD deficiency and is considered pathogenic (Andresen 1996, Hoffman 2012, Spiekerkoetter 2010). The p.Arg366His variant is listed in ClinVar (Variation ID: 203580) and observed in the general population with low overall allele frequency of 0.003% (8/282,884 alleles) in the Genome Aggregation Database. The arginine at codon 366 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.975). Based on the above information, the p.Arg366His variant is considered 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. PMID: 9973285. 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. PMID: 8845838. Antunes AP et al. Intermittent rhabdomyolysis with adult onset associated with a mutation in the ACADVL gene. J Clin Neuromuscul Dis. 2013 Dec;15(2):69-72. PMID: 24263034. 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. PMID: 27246109. 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. PMID: 20060901. Hoffman 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. PMID: 21932095. 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. PMID: 20547398.

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

From Illumina Laboratory Services, Illumina, SCV000915777.1

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

Description

The ACADVL c.1097G>A (p.Arg366His) missense variant has been reported in at least four studies in which it is identified in at least seven individuals with VLCAD deficiency including in a homozygous state in one individual, in a compound heterozygous state in three individuals, in cis with another missense variant, both of which are in trans with a third missense variant in one individual, and in a heterozygous state in two individuals in whom it is unclear if they carry a second variant (Andresen et al. 1999; Boneh et al. 2006; Antunes et al. 2013; Evans et al. 2016). The p.Arg366His variant was absent from 100 control alleles and is reported at a frequency of 0.000098 in the South Asian population of the Genome Aggregation Database. Biochemical studies confirmed the VLCAD deficiency in all patients. Western blot analysis revealed reduced or barely detectable protein levels in fibroblasts from a patient carrying the p.Arg366His variant (Andresen et al. 1999). Several studies note that the variant is associated with a milder phenotype (Gobin-Limballe et al. 2010; Antunes et al. 2013; Brown et al. 2014). Structural analysis of the VLCAD protein suggests that the p.Arg366His variant would induce major structural alterations in substrate-binding, FAD-binding and in enzyme monomer-monomer interactions (Gobin-Limballe et al. 2010). The Arg366 site is thought to be a potential hotspot for variants (Andresen et al. 1999). Based on the collective evidence, the p.Arg366His 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 Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001364915.2

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

Description

The NM_000018.3:c.1097G>A (NP_000009.1:p.Arg366His) [GRCH38: NC_000017.11:g.7223152G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. 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 Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001443688.1

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

Description

This variant has been observed as homozygous or compound heterozygous change in several individuals affected with very long chain acyl-CoA dehydrogenase (VLCAD)(PMID: 9973285, 20060901, 24263034, 27246109). This variant is also known as p.Arg326His in the literature. ClinVar contains an entry for this variant (Variation ID: 203580). A different amino acid change at the same residue (p.Arg366Cys) have been reported in association with VLCAD deficiency (PMID 8845838, 21932095) supporting the functional importance of this region of the protein. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (8/282884) and thus is presumed to be rare. The c.1166G>A (p.Arg389His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1166G>A (p.Arg389His) variant is classified as Pathogenic.

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

From Natera, Inc., SCV001455139.1

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

From ClinGen ACADVL Variant Curation Expert Panel, ClinGen, SCV002576746.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

The c.1097G>A (p.Arg366His) variant in ACADVL has been reported in the literature in patients with VLCADD or increased C14:1 acylcarnitine levels (PP4; PMID: 9973285, 20060901, 27246109, 24263034, 32558070). The variant has been detected as homozygote (PMID:24263034), or compound heterozygote with truncating/pathogenic variants, however without phase confirmation (PMID: 32558070, 27246109, 20060901, PM3). The highest population minor allele frequency in gnomAD is 0.0001 in the South Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). This variant resides within a region defined as a mutational hotspot by the ClinGen ACADVL Variant Curation Expert Panel (PMID: 9973285, 20060901, PM1). The computational predictor REVEL gives a score of 0.98, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PP4, PM1, PM3, PM2_Supporting, PP3).

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

From Baylor Genetics, SCV004214062.2

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

Last Updated: Jun 17, 2024