NM_000018.4(ACADVL):c.364A>G (p.Asn122Asp) AND Very long chain acyl-CoA dehydrogenase deficiency

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jul 9, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000690847.4

Allele description [Variation Report for NM_000018.4(ACADVL):c.364A>G (p.Asn122Asp)]

NM_000018.4(ACADVL):c.364A>G (p.Asn122Asp)

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.364A>G (p.Asn122Asp)
HGVS:
  • NC_000017.11:g.7220945A>G
  • NG_007975.1:g.6112A>G
  • NG_008391.2:g.4106T>C
  • NM_000018.4:c.364A>GMANE SELECT
  • NM_001033859.2:c.298A>G
  • NM_001270447.1:c.433A>G
  • NM_001270448.1:c.136A>G
  • NP_000009.1:p.Asn122Asp
  • NP_001029031.1:p.Asn100Asp
  • NP_001257376.1:p.Asn145Asp
  • NP_001257377.1:p.Asn46Asp
  • NC_000017.10:g.7124264A>G
  • NM_000018.3:c.364A>G
Protein change:
N100D
Links:
dbSNP: rs1057520088
NCBI 1000 Genomes Browser:
rs1057520088
Molecular consequence:
  • NM_000018.4:c.364A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001033859.2:c.298A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270447.1:c.433A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270448.1:c.136A>G - 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
SCV000818576Invitaecriteria provided, single submitter
Likely pathogenic
(Jul 9, 2020)
germlineclinical testing

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

SCV000883341ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Sep 26, 2018)
germlineclinical testing

Citation Link,

SCV001364887Wong 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]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
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

Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches.

Gobin-Limballe S, McAndrew RP, Djouadi F, Kim JJ, Bastin J.

Biochim Biophys Acta. 2010 May;1802(5):478-84. doi: 10.1016/j.bbadis.2010.01.001. Epub 2010 Jan 12.

PubMed [citation]
PMID:
20060901
PMCID:
PMC3401415
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000818576.3

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

Description

This sequence change replaces asparagine with aspartic acid at codon 122 of the ACADVL protein (p.Asn122Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous or in combination with another ACADVL variant in individuals affected with very long chain acyl-CoA dehydrogenase deficiency (PMID: 20060901). ClinVar contains an entry for this variant (Variation ID: 376917). 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: Probably Damaging; Align-GVGD: Class C1). 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. 5

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

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV000883341.2

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

Description

The ACADVL c.364A>G; p.Asn122Asp variant (rs1057520088) has been reported in an individual with VLCAD deficiency who was homozygous for the variant, and cultured fibroblasts from this individual showed extremely low residual VLCAD protein levels and severe FAO-deficiency (Gobin-Limballe 2010, Gobin-Limballe 2007). Additionally, our laboratory has previously identified this variant in an affected individual who was apparent homozygous for the variant. This variant is reported as pathogenic in ClinVar (Variation ID: 376917), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database). Based on available information, this variant is considered pathogenic. REFERENCES 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. 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 Dec;81(6):1133-43.

#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, SCV001364887.2

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

Description

The NM_000018.3:c.364A>G (NP_000009.1:p.Asn122Asp) [GRCH38: NC_000017.11:g.7220945A>G] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 20060901. 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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