NM_000018.4(ACADVL):c.1226C>T (p.Thr409Met) AND Very long chain acyl-CoA dehydrogenase deficiency

Clinical significance:Uncertain significance (Last evaluated: Jun 15, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000020069.3

Allele description [Variation Report for NM_000018.4(ACADVL):c.1226C>T (p.Thr409Met)]

NM_000018.4(ACADVL):c.1226C>T (p.Thr409Met)

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.1226C>T (p.Thr409Met)
HGVS:
  • NC_000017.11:g.7223687C>T
  • NG_007975.1:g.8854C>T
  • NM_000018.4:c.1226C>T
  • NM_001270448.1:c.998C>T
  • NP_000009.1:p.Thr409Met
  • NP_001257377.1:p.Thr333Met
  • NC_000017.10:g.7127006C>T
  • NM_000018.2:c.1226C>T
  • NM_000018.3:c.1226C>T
Protein change:
T333M
Links:
dbSNP: rs113994169
NCBI 1000 Genomes Browser:
rs113994169
Molecular consequence:
  • NM_000018.3:c.1226C>T - 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
SCV000040367GeneReviewsno assertion criteria providedpathologic
(Sep 22, 2011)
not providedcuration

SCV000654921Invitaecriteria provided, single submitter
Uncertain significance
(Jun 15, 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 providednot providednot providednot providednot providednot providednot providednot providedcuration

Citations

PubMed

Infants suspected to have very-long chain acyl-CoA dehydrogenase deficiency from newborn screening.

Merritt JL 2nd, Vedal S, Abdenur JE, Au SM, Barshop BA, Feuchtbaum L, Harding CO, Hermerath C, Lorey F, Sesser DE, Thompson JD, Yu A.

Mol Genet Metab. 2014 Apr;111(4):484-92. doi: 10.1016/j.ymgme.2014.01.009. Epub 2014 Jan 23.

PubMed [citation]
PMID:
24503138

Abstracts of the SSIEM 2014 Annual Symposium, 2-5 September, 2014, Innsbruck, Austria.

[No authors listed]

J Inherit Metab Dis. 2014 Sep;37 Suppl 1:27-185. doi: 10.1007/s10545-014-9740-5. No abstract available.

PubMed [citation]
PMID:
25085675
See all PubMed Citations (3)

Details of each submission

From GeneReviews, SCV000040367.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

Converted during submission to Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

From Invitae, SCV000654921.2

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

Description

This sequence change replaces threonine with methionine at codon 409 of the ACADVL protein (p.Thr409Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs113994169, ExAC 0.02%). This variant has been identified in multiple asymptomatic Hawaiian newborns (PMID: 24503138) and Maori and Pacific Islander newborns in New Zealand with abnormal newborn screening for VLCAD deficiency (PMID: 25085675). Of the 6 asymptomatic Hawaiian newborns that were homozygous for this variant, the majority had normal confirmatory plasma acylcarnitne analysis (PMID: 24503138). Fatty acid oxidation probe analysis was normal in New Zealand newborns that were homozygous for this variant but newborns who were compound heterozygous for this variant and a pathogenic variant had mild fatty acid oxidation impairment at 41 degrees centigrade (PMID: 25085675, abstract P-035). In addition, retrospective review of newborn screening cases of individuals that were below the NZ C14:1 cutoff but above the R4S cutoff (0.9 - 2.4μmol/L), showed that this variant is prevalent in the Maori population and was significantly associated with NBS C14:1 levels in this range but did not appear to be associated with increased prevalence of VLCADD clinical symptoms. ClinVar contains an entry for this variant (Variation ID: 21013). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a prevalent missense change in the Maori and Pacific Islander populations that is associated with a mild biochemical defect on newborn screening but most often normal confirmatory biochemical analysis. In the absence of additional functional and clinical data, this change has been classified as a Variant of Uncertain Significance.

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

Last Updated: Mar 30, 2019

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