NM_000018.4(ACADVL):c.553G>A (p.Gly185Ser) AND Very long chain acyl-CoA dehydrogenase deficiency

Clinical significance:Pathogenic (Last evaluated: Jul 22, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000412436.8

Allele description [Variation Report for NM_000018.4(ACADVL):c.553G>A (p.Gly185Ser)]

NM_000018.4(ACADVL):c.553G>A (p.Gly185Ser)

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.553G>A (p.Gly185Ser)
Other names:
p.G185S:GGT>AGT
HGVS:
  • NC_000017.11:g.7221613G>A
  • NG_007975.1:g.6780G>A
  • NG_008391.2:g.3438C>T
  • NM_000018.4:c.553G>AMANE SELECT
  • NM_001033859.2:c.487G>A
  • NM_001270447.1:c.622G>A
  • NM_001270448.1:c.325G>A
  • NP_000009.1:p.Gly185Ser
  • NP_001029031.1:p.Gly163Ser
  • NP_001257376.1:p.Gly208Ser
  • NP_001257377.1:p.Gly109Ser
  • NC_000017.10:g.7124932G>A
  • NM_000018.2:c.553G>A
  • NM_000018.3:c.553G>A
  • NM_000018.4:c.553G>A
  • NM_001033859.1:c.487G>A
  • P49748:p.Gly185Ser
Protein change:
G109S
Links:
UniProtKB: P49748#VAR_000335; dbSNP: rs545215807
NCBI 1000 Genomes Browser:
rs545215807
Molecular consequence:
  • NM_000018.4:c.553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001033859.2:c.487G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270447.1:c.622G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270448.1:c.325G>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
SCV000485276Counsylno assertion criteria providedLikely pathogenic
(Oct 13, 2016)
unknownclinical testing

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

SCV000654958Invitaecriteria provided, single submitter
Pathogenic
(Oct 10, 2020)
germlineclinical testing

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

SCV000883349ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Jan 17, 2020)
germlineclinical testing

Citation Link,

SCV001364892Wong 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]

SCV001810246Nilou-Genome Labcriteria provided, single submitter
Pathogenic
(Jul 22, 2021)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Bezafibrate can be a new treatment option for mitochondrial fatty acid oxidation disorders: evaluation by in vitro probe acylcarnitine assay.

Yamaguchi S, Li H, Purevsuren J, Yamada K, Furui M, Takahashi T, Mushimoto Y, Kobayashi H, Hasegawa Y, Taketani T, Fukao T, Fukuda S.

Mol Genet Metab. 2012 Sep;107(1-2):87-91. doi: 10.1016/j.ymgme.2012.07.004. Epub 2012 Jul 14.

PubMed [citation]
PMID:
22841441

Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy.

Gobin-Limballe S, Djouadi F, Aubey F, Olpin S, Andresen BS, Yamaguchi S, Mandel H, Fukao T, Ruiter JP, Wanders RJ, McAndrew R, Kim JJ, Bastin J.

Am J Hum Genet. 2007 Dec;81(6):1133-43. Epub 2007 Oct 29.

PubMed [citation]
PMID:
17999356
PMCID:
PMC2276345
See all PubMed Citations (7)

Details of each submission

From Counsyl, SCV000485276.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000654958.3

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

Description

This sequence change replaces glycine with serine at codon 185 of the ACADVL protein (p.Gly185Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs545215807, ExAC 0.01%). This variant has been reported in combination with other ACADVL variants in the fibroblasts from individuals affected with VLCADD (PMID: 17999356, 20060901, 22841441). ClinVar contains an entry for this variant (Variation ID: 203595). Fibroblasts from affected individuals showed diminished VLCAD protein expression and enzyme activity (PMID: 17999356, 20060901). In addition, fibroblasts from an individual heterozygous of this variant has been shown to have 29% residual enzyme activity (PMID: 21932095). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the ACADVL gene (PMID: 20060901), suggest that this missense change is likely to be deleterious. However, these predictions have not been confirmed by published functional studies. 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, SCV000883349.3

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

Description

The ACADVL c.553G>A, p.Gly185Ser variant (rs545215807), also known as Gly145Ser, has been reported in multiple individuals with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Andresen 1999, Gobin-Limballe 2007, Yamaguchi 2012). Multiple affected individuals with this variant were also found to carry a second pathogenic variant (Gobin-Limballe 2007, Yamaguchi 2012). The p.Gly185Ser variant is listed in ClinVar (Variation ID: 203595) and is observed on only three chromosomes in the Genome Aggregation Database (3/251456 alleles). The glycine at position 185 is highly conserved (Alamut v2.10), and it occurs in the substrate binding cavity of the VLCAD enzyme (Hoffman 2012). Functional characterization of patient fibroblasts carrying this variant indicates a substantial decrease in VLCAD protein levels (Andresen 1999, Gobin-Limballe 2010) and enzymatic activity compared to wildtype (Gobin-Limballe 2007, Hoffman 2012). Based on available information, the p.Gly185Ser variant is considered to be pathogenic. References: Andresen B et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999; 64(2):479-94. Gobin-Limballe S et al. Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy. Am J Hum Genet. 2007; 81(6):1133-43. 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; 1802(5):478-84. Hoffman L et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012; 35(2):269-77. Yamaguchi S et al. Bezafibrate can be a new treatment option for mitochondrial fatty acid oxidation disorders: evaluation by in vitro probe acylcarnitine assay. Mol Genet Metab. 2012; 107(1-2):87-91.

#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, SCV001364892.2

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

Description

The NM_000018.3:c.553G>A (NP_000009.1:p.Gly185Ser) [GRCH38: NC_000017.11:g.7221613G>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 Nilou-Genome Lab, SCV001810246.1

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

Last Updated: Sep 7, 2021

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