17-17213796-CTG-C

Position:

• chr17-17213796-CTG-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The ENST00000285071.9(FLCN):​c.1597_1598del​(p.Gln533GlufsTer68) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q533Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FLCN ENST00000285071.9 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.65

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-17213796-CTG-C is Pathogenic according to our data. Variant chr17-17213796-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 234040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17213796-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.1597_1598del	p.Gln533GlufsTer68	frameshift_variant	14/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.1597_1598del	p.Gln533GlufsTer68	frameshift_variant	14/14	1	NM_144997.7	ENSP00000285071	P1
MPRIP	ENST00000578209.5	c.*18-3688_*18-3687del		intron_variant		3		ENSP00000464276

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461888 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2021

The c.1597_1598delCA pathogenic mutation, located in coding exon 11 of the FLCN gene, results from a deletion of two nucleotides at nucleotide positions 1597 to 1598, causing a translational frameshift with a predicted alternate stop codon (p.Q553Efs*68). This frameshift occurs at the 3' end of FLCN, is not expected to trigger nonsense-mediated mRNA decay, impacts only the last 8%/47 amino acids of the protein, and elongates the FLCN protein by 21 amino acids. Frameshifts are typically deleterious in nature and there are multiple similar alterations classified as pathogenic including FLCN c.1616dupT (p.A541Cfs*61) and FLCN c.1579_1580insA (p.R527Qfs*75) (Ambry Internal Data; Furuya M et al. Am J Surg Pathol, 2012 Apr;36:589-600; Yang CY et al. J Postgrad Med;59:321-3; Liu L et al. Biomed Res Int, 2017 Jul;2017:8751384; Hou X et al. BMC Med Genet, 2018 01;19:14). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with FLCN-related disease (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Birt-Hogg-Dube syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 21, 2023

This sequence change results in a frameshift in the FLCN gene (p.Gln533Glufs*68). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the FLCN protein and extend the protein by 20 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individuals with Birt-Hogg-Dubé syndrome (PMID: 20403193; Invitae). This variant is also known as 2052_2053del. ClinVar contains an entry for this variant (Variation ID: 234040). This variant disrupts the FNIP1/2 interaction domain, which has been shown to be important for AMPK-mediated mTOR signaling pathways (PMID: 17028174, 18403135, 18663353, 22977732). While functional studies have not been performed to directly test the effect of this variant on FLCN protein function, this suggests that disruption of this region of the protein may be causative of disease. This variant disrupts a region of the FLCN protein in which other variant(s) (p.Trp553Arg) have been determined to be pathogenic (Invitae; external communications). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs876660810; hg19: chr17-17117110;