ClinVar Genomic variation as it relates to human health

Variant summary: FLCN c.1285dupC (p.His429ProfsX27) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00011 in 245324 control chromosomes (gnomAD). c.1285dupC has been reported in the literature in multiple individuals affected with Birt-Hogg-Dube Syndrome (Schmidt_2005, Hoshika_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports this variant has an impact on protein function (Hoshika_2016). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

This frameshift variant alters the translational reading frame of the FLCN mRNA and causes the premature termination of FLCN protein synthesis. In the published literature, the variant has been reported in several individuals and families with Birt-Hogg-Dube Syndrome (PMIDs: 12204536 (2002), 12471204 (2002), 17496196 (2007), 18505456 (2008), 26028485 (2015), 27220747 (2016), 27734835 (2017), 27905298 (2016), 29357828 (2018), 29548312 (2018), and 30360018 (2019)). Functional studies found that this variant significantly impaired FLCN protein stability and function (PMIDs: 21538689 (2011) and 27905298 (2016)). Based on the available information, this variant is classified as pathogenic.

This sequence change creates a premature translational stop signal (p.His429Profs*27) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Birt-Hogg-Dubé (BHD) syndrome (PMID: 12204536, 12471204, 17496196, 20522427). It has also been observed to segregate with disease in related individuals. This variant is also known as 1733insC, 1740dupC, and 1277insC. ClinVar contains an entry for this variant (Variation ID: 3363). For these reasons, this variant has been classified as Pathogenic.

PVS1, PM2, PP5

The c.1285dupC;p.(His429Profs*27) is a null frameshift variant (NMD) in the FLCN gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 3363; PMID: 12471204; PMID: 20522427; PMID: 17496196; PMID: 12204536)PS4_moderate. This variant is not present in population databases (rs80338682- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.

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 (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 variable expressivity (OMIM). (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) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (6 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are at least 10 NMD-predicted likely pathogenic/pathogenic variants in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The c.1285dupC variant, along with the c.1285delC variant, are the most common pathogenic variants and have been reported in 20%-24% of families with Birt-Hogg-Dube syndrome (GeneReviews). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: inactivates gene expression, disrupts protein stability, inhibits tumor suppression, and down-regulates multiple genes involved in TGF-beta signaling (Hong et al., 2010a; Hong et al., 2010b; Nahorski et al., 2011); Also known as 1733insC; This variant is associated with the following publications: (PMID: 21209915, 23784378, 23416984, 12204536, 27229674, 28152038, 12471204, 21538689, 22146830, 23995526, 24346394, 20573232, 25594584, 19850877, 20618353, 18505456, 27220747, 27734835, 28558743, 28690286, 28151982, 29357828, 30360018, 29548312, 28724667, 26387484, 26028485, 28869776, 22148048, 20522427, 31019283, 32782288, 33726816, 34008892, 30696655)

PP1, PP4, PS3_supporting, PS4_moderate, PVS1

The FLCN c.1285dupC; p.His429ProfsTer27 variant (rs80338682), also known as 9C, 1733insC, 1740dupC, and 1277insC, is a well-known pathogenic variant that occurs in the mutational sequence hot-spot of eight cytosine nucleotides in exon 11 on the FLCN gene. Both c.1285delC and c.1285dupC have been reported in several patients diagnosed with Birt-Hogg-Dube syndrome (Khoo 2002, Lee 2019, Nahorski 2011, Nickerson 2002, Sattler 2018). The c.1285dupC variant is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 3363). This variant causes a frameshift by duplicating a single nucleotide, 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: Khoo SK et al. Clinical and genetic studies of Birt-Hogg-Dube syndrome. J Med Genet. 2002 Dec;39(12):906-12. PMID: 12471204. Lee JH et al. Birt-Hogg-Dube syndrome in Korean: clinicoradiologic features and long term follow-up. Korean J Intern Med. 2019 Jul;34(4):830-840. PMID: 30360018. Nahorski MS et al. Birt Hogg-Dube syndrome-associated FLCN mutations disrupt protein stability. Hum Mutat. 2011 Aug;32(8):921-9. PMID: 21538689. Nickerson ML et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell. 2002 Aug;2(2):157-64. PMID: 12204536. Sattler EC et al. Delayed diagnosis of Birt-Hogg-Dube syndrome due to marked intrafamilial clinical variability: a case report. BMC Med Genet. 2018 Mar 16;19(1):45. PMID: 29548312.

The c.1285dupC pathogenic mutation, located in coding exon 8 of the FLCN gene, results from a duplication of C at nucleotide position 1285, causing a translational frameshift with a predicted alternate stop codon (p.H429Pfs*27). This recurrent mutation has been reported in multiple families affected with Birt-Hogg-Dub&eacute; syndrome and was shown to result in significant impairment of FLCN protein stability and function (Nickerson ML et al. Cancer Cell. 2002 Aug;2:157-64; Khoo SK et al. J. Med. Genet. 2002 Dec;39:906-12; Nahorski MS et al. Hum. Mutat. 2011 Aug;32:921-9; Nishida C et al. Respir. Med. 2015 Jul;109:923-5; Furuya M et al. Clin. Genet. 2016 Nov;90:403-412; Rossing M et al. J. Hum. Genet. 2017 Feb;62:151-157; Lee JH et al. Korean J. Intern. Med. 2018 Oct). In addition to the clinical data presented in the literature, 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.

Criteria applied: PVS1,PS4_MOD,PS3_SUP,PP1,PP4

FLCN: PVS1, PP1:Strong, PS4:Moderate, PP4

The FLCN c.1285dupC variant is predicted to result in a frameshift and premature protein termination (p.His429Profs*27). This variant has been reported to be causative for Birt-Hogg-Dubé syndrome (Khoo et al. 2002. PubMed ID: 12471204, listed as 1733insC; Nahorski et al. 2011. PubMed ID: 21538689; Luijten et al. 2013. PubMed ID: 23784378). This variant is reported in 0.044% of alleles in individuals of African descent in gnomAD. However, the quality of data at this genomic position is questionable and allele frequency data should be interpreted with caution. This variant been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3363/). Frameshift variants in FLCN are expected to be pathogenic. This variant is interpreted as pathogenic.