rs879255677
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_144997.7(FLCN):c.1334_1335insGAGGTCCACGCAGCCGC(p.Leu449GlnfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
FLCN
NM_144997.7 frameshift
NM_144997.7 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.05
Genes affected
FLCN (HGNC:27310): (folliculin) This gene is located within the Smith-Magenis syndrome region on chromosome 17. Mutations in this gene are associated with Birt-Hogg-Dube syndrome, which is characterized by fibrofolliculomas, renal tumors, lung cysts, and pneumothorax. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
MPRIP (HGNC:30321): (myosin phosphatase Rho interacting protein) Enables cadherin binding activity. Predicted to be involved in actin filament organization. Located in actin cytoskeleton and cytosol. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 17-17215282-T-TGCGGCTGCGTGGACCTC is Pathogenic according to our data. Variant chr17-17215282-T-TGCGGCTGCGTGGACCTC is described in ClinVar as [Pathogenic]. Clinvar id is 253249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLCN | NM_144997.7 | c.1334_1335insGAGGTCCACGCAGCCGC | p.Leu449GlnfsTer25 | frameshift_variant | 12/14 | ENST00000285071.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLCN | ENST00000285071.9 | c.1334_1335insGAGGTCCACGCAGCCGC | p.Leu449GlnfsTer25 | frameshift_variant | 12/14 | 1 | NM_144997.7 | P1 | |
MPRIP | ENST00000578209.5 | c.*18-2207_*18-2191dup | intron_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461834Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5AN XY: 727208
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GnomAD4 genome ? Cov.: 32
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Birt-Hogg-Dube syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 07, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 30, 2023 | This sequence change creates a premature translational stop signal (p.Leu449Glnfs*25) in the FLCN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with renal cell carcinoma (PMID: 18794106, 19802896). This variant is also known as c.1833_1849dup17. ClinVar contains an entry for this variant (Variation ID: 253249). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Birt-Hogg-Dube syndrome (BHDS) (MIM#135150) and primary spontaneous pneumothorax (MIM#173600). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have intra- and inter-familial variable expressivity (OMIM; PMID: 15852235; 30586397). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic in association with BHDS and hereditary cancer predisposing syndrome (ClinVar), as well as in four BHDS families in a conference abstract with limited information (PMID: 21506000). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Jul 18, 2016 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 25, 2023 | The FLCN c.1318_1334dup (p.Leu449Glnfs*25) variant alters the translational reading frame of the FLCN mRNA and causes the premature termination of FLCN protein synthesis. This variant has been reported in the published literature in an individual with renal cell carcinoma (PMID: 18794106 (2008)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 11, 2023 | The FLCN c.1318_1334dup; p.Leu449GlnfsTer25 variant (rs879255677) is reported in the literature in at least one individual with a Birt-Hogg-Dube-associated phenotype (Savatt 2022). This variant is also reported in ClinVar (Variation ID: 253249). It is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by inserting 17 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Savatt JM et al. Frequency of truncating FLCN variants and Birt-Hogg-Dube-associated phenotypes in a health care system population. Genet Med. 2022 Sep;24(9):1857-1866. PMID: 35639097. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 18, 2018 | The c.1318_1334dup17 variant in the FLCN gene has not been reported previously as a pathogenicvariant, nor as a benign variant, to our knowledge. This variant causes a frameshift starting with codonLeucine 449, changes this amino acid to a Glutamine residue and creates a premature Stop codon atposition 25 of the new reading frame, denoted p.Leu449GlnfsX25. The c.1318_1334dup17 variant ispredicted to cause loss of normal protein function either through protein truncation or nonsensemediatedmRNA decay. Based on currently available evidence, we consider c.1318_1334dup17 to bepathogenic, and its presence consistent with a diagnosis of Birt-Hogg-Dube syndrome. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 18, 2022 | The c.1318_1334dup17 variant, located in coding exon 9 of the FLCN gene, results from a duplication of GAGGTCCACGCAGCCGC at nucleotide position 1318, causing a translational frameshift with a predicted alternate stop codon (p.L449Qfs*25). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at