NM_001270448.1(ACADVL):c.875A>C (p.Gln292Pro) AND Very long chain acyl-CoA dehydrogenase deficiency

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(2) (Last evaluated: Apr 24, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000558671.1

Allele description [Variation Report for NM_001270448.1(ACADVL):c.875A>C (p.Gln292Pro)]

NM_001270448.1(ACADVL):c.875A>C (p.Gln292Pro)

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_001270448.1(ACADVL):c.875A>C (p.Gln292Pro)
HGVS:
  • NC_000017.11:g.7223158A>C
  • NG_007975.1:g.8325A>C
  • NM_000018.4:c.1103A>C
  • NM_001270447.1:c.1172A>C
  • NM_001270448.1:c.875A>C
  • NP_000009.1:p.Gln368Pro
  • NP_001257376.1:p.Gln391Pro
  • NP_001257377.1:p.Gln292Pro
  • NC_000017.10:g.7126477A>C
  • NM_000018.3:c.1103A>C
Protein change:
Q292P
Links:
dbSNP: rs776063244
NCBI 1000 Genomes Browser:
rs776063244
Molecular consequence:
  • NM_000018.3:c.1103A>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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
SCV000654918Invitaecriteria provided, single submitter
Uncertain significance
(Feb 6, 2017)
germlineclinical testing

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

SCV000791058Counsylcriteria provided, single submitter
Uncertain significance
(Apr 24, 2017)
unknownclinical testing

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

Citation Link,

SCV000891175Molecular Diagnostics Laboratory,M Health: University of Minnesotacriteria provided, single submitter
Likely pathogenic
(Mar 13, 2017)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyes1not providednot provided1not providedclinical testing
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.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States.

Miller MJ, Burrage LC, Gibson JB, Strenk ME, Lose EJ, Bick DP, Elsea SH, Sutton VR, Sun Q, Graham BH, Craigen WJ, Zhang VW, Wong LJ.

Mol Genet Metab. 2015 Nov;116(3):139-45. doi: 10.1016/j.ymgme.2015.08.011. Epub 2015 Sep 2.

PubMed [citation]
PMID:
26385305
PMCID:
PMC4790081
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000654918.1

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

Description

This sequence change replaces glutamine with proline at codon 368 of the ACADVL protein (p.Gln368Pro). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is present in population databases (rs776063244, ExAC 0.001%). This variant has been reported in individuals with abnormal newborn screening results suggestive of VLCADD (PMID: 26385305). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in individuals likely affected, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From Counsyl, SCV000791058.1

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

From Molecular Diagnostics Laboratory,M Health: University of Minnesota, SCV000891175.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

Last Updated: Mar 30, 2019

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