NM_000018.4(ACADVL):c.1349G>A (p.Arg450His) AND not provided

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jul 19, 2019)

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:
RCV000724571.3

Allele description [Variation Report for NM_000018.4(ACADVL):c.1349G>A (p.Arg450His)]

NM_000018.4(ACADVL):c.1349G>A (p.Arg450His)

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.1349G>A (p.Arg450His)
Other names:
R410H
HGVS:
  • NC_000017.11:g.7223984G>A
  • NG_007975.1:g.9151G>A
  • NG_008391.2:g.1067C>T
  • NG_033038.1:g.15561C>T
  • NM_000018.4:c.1349G>AMANE SELECT
  • NM_001033859.2:c.1283G>A
  • NM_001270447.1:c.1418G>A
  • NM_001270448.1:c.1121G>A
  • NP_000009.1:p.Arg450His
  • NP_001029031.1:p.Arg428His
  • NP_001257376.1:p.Arg473His
  • NP_001257377.1:p.Arg374His
  • NC_000017.10:g.7127303G>A
  • NM_000018.2:c.1349G>A
  • NM_000018.3:c.1349G>A
  • P49748:p.Arg450His
Protein change:
R374H; ARG410HIS
Links:
UniProtKB: P49748#VAR_000355; OMIM: 609575.0010; OMIM: 609575.0014; dbSNP: rs118204016
NCBI 1000 Genomes Browser:
rs118204016
Molecular consequence:
  • NM_000018.4:c.1349G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001033859.2:c.1283G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270447.1:c.1418G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270448.1:c.1121G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000225986EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
Likely pathogenic
(Jan 27, 2015)
germlineclinical testing

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

Citation Link,

SCV000884952ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Apr 23, 2018)
germlineclinical testing

Citation Link,

SCV001811368GeneDxcriteria provided, single submitter
Pathogenic
(Jul 19, 2019)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown2not providednot providednot providednot providedclinical testing

Citations

PubMed

Myopathic form of very-long chain acyl-coa dehydrogenase deficiency: evidence for temperature-sensitive mild mutations in both mutant alleles in a Japanese girl.

Fukao T, Watanabe H, Orii K, Takahashi Y, Hirano A, Kondo T, Yamaguchi S, Aoyama T, Kondo N.

Pediatr Res. 2001 Feb;49(2):227-31.

PubMed [citation]
PMID:
11158518

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 EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000225986.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided2not providednot providednot provided

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV000884952.1

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

Description

The ACADVL c.1349G>A; p.Arg450His variant (rs118204016), also known as Arg410His for traditional nomenclature, is reported multiple times in the literature in association with VLCAD deficiency and is reported both in the homozygous and compound heterozygous states in affected individuals (Andresen 1999, Fukao 2001, Gobin-Limballe 2010, Kang 2018, Ohashi 2004, Smelt 1998, Zhang 2014). Additionally, functional analyses of the variant protein show decreased expression and enzymatic activity (Fukao 2001, Smelt 1998). This variant is reported in ClinVar (Variation ID: 1634) and found in the general population with a low overall allele frequency of 0.003% (8/277108 alleles) in the Genome Aggregation Database. The arginine at codon 450 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this 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. Fukao T et al. Myopathic form of very-long chain acyl-coa dehydrogenase deficiency: evidence for temperature-sensitive mild mutations in both mutant alleles in a Japanese girl. Pediatr Res. 2001 Feb;49(2):227-31. 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. Kang E et al. Clinical and genetic characteristics of patients with fatty acid oxidation disorders identified by newborn screening. BMC Pediatr. 2018 Mar 8;18(1):103. Ohashi Y et al. A new diagnostic test for VLCAD deficiency using immunohistochemistry. Neurology. 2004 Jun 22;62(12):2209-13. Smelt AH et al. Very long chain acyl-coenzyme A dehydrogenase deficiency with adult onset. Ann Neurol. 1998 Apr;43(4):540-4. Zhang RN et al. Clinical features and mutations in seven Chinese patients with very long chain acyl-CoA dehydrogenase deficiency. World J Pediatr. 2014 May;10(2):119-25.

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

From GeneDx, SCV001811368.1

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

Description

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32581362, 31130284, 30840296, 11158518, 20060901, 24801231, 29519241, 28980192, 29552494, 27246109, 25652019, 9973285, 9546340, 15210884)

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

Last Updated: Sep 24, 2021

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