NM_000018.3(ACADVL):c.1246G>A (p.Ala416Thr) AND Very long chain acyl-CoA dehydrogenase deficiency

Clinical significance:Pathogenic (Last evaluated: May 3, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000001700.4

Allele description [Variation Report for NM_000018.3(ACADVL):c.1246G>A (p.Ala416Thr)]

NM_000018.3(ACADVL):c.1246G>A (p.Ala416Thr)

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_000018.3(ACADVL):c.1246G>A (p.Ala416Thr)
HGVS:
  • NC_000017.11:g.7223707G>A
  • NG_007975.1:g.8874G>A
  • NM_000018.3:c.1246G>A
  • NP_000009.1:p.Ala416Thr
  • NC_000017.10:g.7127026G>A
Protein change:
A416T; ALA416THR
Links:
OMIM: 609575.0013; dbSNP: rs118204018
NCBI 1000 Genomes Browser:
rs118204018
Molecular consequence:
  • NM_000018.3:c.1246G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Very long chain acyl-CoA dehydrogenase deficiency (VLCAD)
Synonyms:
Long chain acyl-CoA dehydrogenase deficiency
Identifiers:
MedGen: C3887523; Orphanet: 26793; OMIM: 201475

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000021856OMIMno assertion criteria providedPathogenic
(Feb 1, 2001)
germlineliterature only

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

SCV000832737Invitaecriteria provided, single submitter
Pathogenic
(May 3, 2018)
germlineclinical testing

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

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

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

Identification and characterization of temperature-sensitive mild mutations in three Japanese patients with nonsevere forms of very-long-chain acyl-CoA dehydrogenase deficiency.

Takusa Y, Fukao T, Kimura M, Uchiyama A, Abo W, Tsuboi Y, Hirose S, Fujioka H, Kondo N, Yamaguchi S.

Mol Genet Metab. 2002 Mar;75(3):227-34.

PubMed [citation]
PMID:
11914034
See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000021856.2

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

Description

In a 14-year-old Japanese girl with very mild manifestations of VLCAD deficiency (201475), Fukao et al. (2001) identified compound heterozygosity for 2 mutations in the ACADVL gene: 1 resulting in an ala416-to-thr (A416T) substitution, and the other resulting in an arg450-to-his (R450H; 609575.0014) substitution. In vitro functional expression studies showed that both mutant proteins retained residual activity at 30 degrees Celsius. Fukao et al. (2001) concluded that the temperature-sensitive mild mutations resulted in the milder phenotype in this patient.

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

From Invitae, SCV000832737.1

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

Description

This sequence change replaces alanine with threonine at codon 416 of the ACADVL protein (p.Ala416Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs118204018, ExAC 0.01%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with a myopathic form of very-long chain acyl-CoA dehydrogenase deficiency (PMID: 11158518). In addition, this variant has been reported in combination with other ACADVL variants in individuals affected with very-long chain acyl-CoA dehydrogenase deficiency (PMID: 11914034, 15210884). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 1633). Experimental studies have shown that this missense change affected the activity of the encoded enzyme although a significant residual activity of 10-20% was retained (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

Last Updated: Mar 30, 2019

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