NM_144997.7(FLCN):c.1286dup (p.His429fs) AND Multiple fibrofolliculomas

Clinical significance:Pathogenic (Last evaluated: Jun 6, 2017)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000239666.2

Allele description [Variation Report for NM_144997.7(FLCN):c.1286dup (p.His429fs)]

NM_144997.7(FLCN):c.1286dup (p.His429fs)

Gene:
FLCN:folliculin [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
17p11.2
Genomic location:
Preferred name:
NM_144997.7(FLCN):c.1286dup (p.His429fs)
HGVS:
  • NC_000017.11:g.17216394dup
  • NG_008001.2:g.25795dup
  • NM_001353229.2:c.1340dup
  • NM_001353230.2:c.1286dup
  • NM_001353231.2:c.1286dup
  • NM_144997.7:c.1286dupMANE SELECT
  • NP_001340158.1:p.His447fs
  • NP_001340159.1:p.His429fs
  • NP_001340160.1:p.His429fs
  • NP_659434.2:p.His429fs
  • LRG_325t1:c.1286dup
  • LRG_325:g.25795dup
  • NC_000017.10:g.17119708dup
  • NM_144997.5:c.1286dupA
  • p.[His429Glnfs*27]
Protein change:
H429fs
Links:
dbSNP: rs879255675
NCBI 1000 Genomes Browser:
rs879255675
Molecular consequence:
  • NM_001353229.2:c.1340dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001353230.2:c.1286dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001353231.2:c.1286dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_144997.7:c.1286dup - frameshift variant - [Sequence Ontology: SO:0001589]
Observations:
1

Condition(s)

Name:
Multiple fibrofolliculomas (BHD)
Synonyms:
BHD syndrome; Fibrofolliculomas with trichodiscomas and acrochordons; Hornstein-Knickenberg syndrome; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007607; MedGen: C0346010; Orphanet: 122; OMIM: 135150

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000298077Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphiacriteria provided, single submitter
    Pathogenic
    (Jul 18, 2016)
    germlineclinical testing

    DGD_Variant_Analysis_Guidelines.docx,

    SCV000549466Invitaecriteria provided, single submitter
    Pathogenic
    (Jun 6, 2017)
    germlineclinical testing

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

    Description

    Clinical Testing

    SCV000298077

    Summary from all submissions

    EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
    not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
    not providedgermlineyes1not 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. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

    PubMed [citation]
    PMID:
    28492532
    PMCID:
    PMC5632818

    Details of each submission

    From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia, SCV000298077.1

    #EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
    1not provided1not providednot providedclinical testingnot provided
    #SampleMethodObservation
    OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
    1germlineyesnot providednot providednot provided1not providednot providednot provided

    From Invitae, SCV000549466.2

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

    Description

    This sequence change inserts 1 nucleotide in exon 11 of the FLCN mRNA (c.1286dupA), causing a frameshift at codon 429. This creates a premature translational stop signal (p.His429Glnfs*27) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLCN are known to be pathogenic. This particular variant has been reported in the literature in an individual with Birt-Hogg-Dubé (BHD) syndrome (PMID: 18234728). This variant is also known as c.1741insA in the literature. A different variant, c.1285dupC (p.His429Profs*27), which results in the same truncated protein as the one observed here, has been reported in individuals affected with BHD syndrome (PMID: 18234728). It has been shown to affect the protein stability and tumor suppressor activity of the FLCN protein in cell culture (PMID: 21538689). 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: Nov 27, 2021

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