rs398124535

Positions:

• chr17-17226251-GAC-GGTG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_144997.7(FLCN):​c.319_320delinsCAC​(p.Val107HisfsTer26) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V107V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLCN NM_144997.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.89

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-17226252-AC-GTG is Pathogenic according to our data. Variant chr17-17226252-AC-GTG is described in ClinVar as [Pathogenic]. Clinvar id is 96483.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.319_320delinsCAC	p.Val107HisfsTer26	frameshift_variant	5/14	ENST00000285071.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLCN	ENST00000285071.9	c.319_320delinsCAC	p.Val107HisfsTer26	frameshift_variant	5/14	1	NM_144997.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 18, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2017	The c.319_320delGTinsCAC variant in the FLCN gene has been reported previously in at least two families with features of Birt-Hogg-Dube syndrome (Toro et al., 2008; Gijezen et al., 2014). This variant causes a frameshift starting with codon Valine 107, changes this amino acid to a Histidine residue and creates a premature Stop codon at position 26 of the new reading frame, denoted p.Val107HisfsX26. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Furthermore, the c.319_320delGTinsCAC variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Based on currently available evidence, we consider c.319_320delGTinsCAC to be pathogenic. -

Birt-Hogg-Dube syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 28, 2021	This sequence change creates a premature translational stop signal (p.Val107Hisfs*26) 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 (ExAC no frequency). This variant has been observed in individual(s) with Birt-Hogg-Dubé syndrome (PMID: 18234728, 22146830, 24910976). It is also known as c.774-5delGTinsCAC. ClinVar contains an entry for this variant (Variation ID: 96483). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2022

The c.319_320delGTinsCAC pathogenic mutation, located in coding exon 2 of the FLCN gene, results from the deletion of two nucleotides and insertion of three nucleotides at positions 319 to 320, causing a translational frameshift with a predicted alternate stop codon (p.V107Hfs*26). This mutation has been reported in multiple families with Birt-Hogg-Dubé syndrome (Toro JR et al J. Med. Genet. 2008 Jun; 45(6):321-31; Houweling AC et al. Br. J. Cancer 2011 Dec;105(12):1912-9; Gijezen LM et al. PLoS ONE 2014 Jun;9(6):e99071). Of note, this alteration is also designated as c.774-5delGTinsCAC in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398124535; hg19: chr17-17129566;