NM_000018.4(ACADVL):c.1349G>A (p.Arg450His) AND Very long chain acyl-CoA dehydrogenase deficiency

Clinical significance:Pathogenic (Last evaluated: Oct 1, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000001701.10

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]

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
SCV000021857OMIMno assertion criteria providedPathogenic
(Feb 1, 2001)
germlineliterature only

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

SCV000654930Invitaecriteria provided, single submitter
Pathogenic
(Oct 1, 2020)
germlineclinical testing

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

SCV001364921Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicinecriteria provided, single submitter
Pathogenic
(Nov 1, 2019)
germlineclinical testing

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

SCV001459255Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Very long chain acyl-coenzyme A dehydrogenase deficiency with adult onset.

Smelt AH, Poorthuis BJ, Onkenhout W, Scholte HR, Andresen BS, van Duinen SG, Gregersen N, Wintzen AR.

Ann Neurol. 1998 Apr;43(4):540-4.

PubMed [citation]
PMID:
9546340

A new diagnostic test for VLCAD deficiency using immunohistochemistry.

Ohashi Y, Hasegawa Y, Murayama K, Ogawa M, Hasegawa T, Kawai M, Sakata N, Yoshida K, Yarita H, Imai K, Kumagai I, Murakami K, Hasegawa H, Noguchi S, Nonaka I, Yamaguchi S, Nishino I.

Neurology. 2004 Jun 22;62(12):2209-13.

PubMed [citation]
PMID:
15210884
See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000021857.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

For discussion of the arg450-to-his (R450H) substitution in the ACADVL gene that was found in compound heterozygous state in a Japanese patient with VLCAD deficiency by Fukao et al. (2001), see 609575.0013.

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

From Invitae, SCV000654930.3

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

Description

This sequence change replaces arginine with histidine at codon 450 of the ACADVL protein (p.Arg450His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (rs118204016, ExAC no frequency). This variant has been reported in several individuals affected with very long chain acyl-CoA dehydrogenase deficiency. Some of these individuals have been shown to be homozygous for this variant or compound heterozygous (in trans) with other deleterious ACADVL variants (PMID: 9546340, 11158518, 15210884, 24801231). This variant is also known as R410H in the literature. ClinVar contains an entry for this variant (Variation ID: 1634). Experimental studies have shown that this missense change reduces ACADVL enzymatic activity (PMID: 11158518). 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, SCV001364921.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

The NM_000018.3:c.1349G>A (NP_000009.1:p.Arg450His) [GRCH38: NC_000017.11:g.7223984G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285; 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

From Natera, Inc., SCV001459255.1

#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: Sep 6, 2021

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