NM_144997.7(FLCN):c.1580G>A (p.Arg527Gln) AND Multiple fibrofolliculomas

Clinical significance:Conflicting interpretations of pathogenicity, Benign(1);Uncertain significance(2) (Last evaluated: Aug 26, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000560552.7

Allele description [Variation Report for NM_144997.7(FLCN):c.1580G>A (p.Arg527Gln)]

NM_144997.7(FLCN):c.1580G>A (p.Arg527Gln)

Gene:
FLCN:folliculin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17p11.2
Genomic location:
Preferred name:
NM_144997.7(FLCN):c.1580G>A (p.Arg527Gln)
HGVS:
  • NC_000017.11:g.17213815C>T
  • NG_008001.2:g.28374G>A
  • NM_001353229.2:c.1634G>A
  • NM_001353230.2:c.1580G>A
  • NM_001353231.2:c.1580G>A
  • NM_144997.7:c.1580G>AMANE SELECT
  • NP_001340158.1:p.Arg545Gln
  • NP_001340159.1:p.Arg527Gln
  • NP_001340160.1:p.Arg527Gln
  • NP_659434.2:p.Arg527Gln
  • LRG_325t1:c.1580G>A
  • LRG_325:g.28374G>A
  • NC_000017.10:g.17117129C>T
  • NM_144997.5:c.1580G>A
Protein change:
R527Q
Links:
dbSNP: rs777826268
NCBI 1000 Genomes Browser:
rs777826268
Molecular consequence:
  • NM_001353229.2:c.1634G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353230.2:c.1580G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353231.2:c.1580G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_144997.7:c.1580G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000632854Invitaecriteria provided, single submitter
Uncertain significance
(Aug 26, 2020)
germlineclinical testing

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

SCV001280627Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Benign
(Jan 13, 2018)
germlineclinical testing

Citation Link,

SCV001481573Baylor Genetics - CSER-TexasKidsCanSeqcriteria provided, single submitter
Uncertain significance
(Sep 10, 2019)
unknownclinical testing

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

Summary from all submissions

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

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Invitae, SCV000632854.5

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

Description

This sequence change replaces arginine with glutamine at codon 527 of the FLCN protein (p.Arg527Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs777826268, ExAC 0.02%). This variant has not been reported in the literature in individuals with FLCN-related disease. 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: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant 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 Illumina Clinical Services Laboratory,Illumina, SCV001280627.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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

From Baylor Genetics - CSER-TexasKidsCanSeq, SCV001481573.2

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

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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

Last Updated: Nov 27, 2021

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