rs121908752

chr7-117535285-T-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_000492.4(CFTR):c.617T>G(p.Leu206Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic,drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L206F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic; drug response reviewed by expert panel P:29 O:1
• Conservation: PhyloP100: 7.62

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837
• PP5: Variant 7-117535285-T-G is Pathogenic according to our data. Variant chr7-117535285-T-G is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 7190.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535285-T-G is described in Lovd as [Pathogenic]. Variant chr7-117535285-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.617T>G	p.Leu206Trp	missense_variant	6/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.617T>G	p.Leu206Trp	missense_variant	6/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000195 AC: 49 AN: 251446 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135898

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000149 AC: 218 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 98 AN XY: 727228

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000167

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74306

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic; drug response

Submissions summary: Pathogenic:29 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 04, 2019	Disease-causing CFTR variant (previously reported for this patient by mass spectrometry genotyping). See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Apr 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000492.3(CFTR):c.617T>G(L206W) is classified as pathogenic in the context of cystic fibrosis and is associated with the non-classic form of disease. Sources cited for classification include the following: PMID 23974870, 15776432, and 18456578. Classification of NM_000492.3(CFTR):c.617T>G(L206W) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jul 22, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 29, 2023	The p.L206W pathogenic mutation (also known as c.617T>G), located in coding exon 6 of the CFTR gene, results from a T to G substitution at nucleotide position 617. The leucine at codon 206 is replaced by tryptophan, an amino acid with similar properties. This mutation has been described in multiple patients with a second mutation confirmed in trans; the majority have pancreatic sufficient cystic fibrosis with intermediate to high sweat chloride levels (Sosnay PR, et al. Nat. Genet. 2013; 45(10):1160-1167). This mutation has also been seen in conjunction with another pathogenic mutation in individuals with CFTR-related disorders, including pancreatitis and congenital absence of the vas deferens (Masson E et al. PLoS ONE, 2013 Aug;8:e73522; Lucarelli M et al. Mol. Med., 2015 Apr;21:257-75; Thomas JM et al. Lancet, 2017 Feb;389:846). In addition, an in vitro assay showed that this mutation results in reduced post-translational processing of the CFTR protein into its mature form (Clain J, et al. Hum Mutat. 2005; 25(4):360-371). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2017	Variant summary: c.617T>G affects a conserved nucleotide, resulting in amino acid change from Leu to Trp. 5/5 in-silico tools predict this variant to be damaging. This variant was found in 27/121506 control chromosomes at a frequency of 0.0002222, which does not exceed the maximal expected frequency of a pathogenic allele (0.0129603). This variant has been reported in multiple CF patients worldwide. Functional studies showed the variant of interest with only about 5% of WT level of [Cl-] transport and defective CFTR processing and maturation (Sosnay_2013 and Van Goor_2014). In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as a Pathogenic. -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Apr 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 206 of the CFTR protein (p.Leu206Trp). This variant is present in population databases (rs121908752, gnomAD 0.06%). This missense change has been observed in individuals with cystic fibrosis (CF) and/or congenital bilateral absence of the vas deferens (CBAVD) and chronic pancreatitis (PMID: 15776432, 20021716, 21520337, 23751316, 23951356, 23974870, 27086061). ClinVar contains an entry for this variant (Variation ID: 7190). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 15776432, 23891399). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2017	The L206W variant in the CFTR gene has been reported previously in individuals with CFTR-related disorders who also harbor additional variants in the CFTR gene (Clain et al., 2005; Claustres et al., 1993). The L206W variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L206W variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In vitro studies of the L206W variant demonstrate significant reduction in CFTR processing in HeLa cells resulting in a decrease in protein production at the cell surface compared to wild type cells (Clain et al., 2005; Van Goor et al., 2014). A missense variant in the same residue (L206F) has been reported previously in association with a CFTR-related disorder (Claustres et al., 2000), supporting the functional importance of this region of the protein. We interpret L206W as a pathogenic variant. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 12, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	CFTR: PVS1, PM1, PS4:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 16, 2020	The CFTR c.617T>G; p.Leu206Trp variant (rs121908752) is reported in the literature in individuals affected with a pancreatic-sufficient form of cystic fibrosis (Bernardino 2000, Clain 2005, de Garcia 2005, Gallati 2009, Ooi 2012, Sosnay 2013, CFTR2 database). Functional characterization of the variant indicates defects in processing and maturation of the CFTR protein (Clain 2005, Sosnay 2013, van Goor 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 7190), and is found in the general population with an overall allele frequency of 0.018% (51/282,838 alleles) in the Genome Aggregation Database. The leucine at codon 206 is highly conserved, and computational analyses (PolyPhen-2, SIFT) predict that the variant is deleterious. Based on available information, the p.Leu206Trp variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org/ Bernardino A et al. Molecular analysis in Brazilian cystic fibrosis patients reveals five novel mutations. Genet Test. 2000; 4(1):69-74. Clain J et al. Misprocessing of the CFTR protein leads to mild cystic fibrosis phenotype. Hum Mutat. 2005; 25(4):360-71. de Garcia J et al. Genotype-phenotype correlation for pulmonary function in cystic fibrosis. Thorax. 2005; 60(7):558-63. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 Nov;19(5):685-94. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012; 11(5):355-62. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. 2013; Nat Genet. 45(10):1160-7. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014; 13(1):29-36. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 29, 2021	The CFTR c.617T>G (p.Leu206Trp) variant (also known as L206W) is associated with pancreatic-sufficient cystic fibrosis (CF), with mild to moderate pulmonary disease and elevated sweat chloride levels. In the published literature, this variant has been reported in individuals affected with CF and congenital bilateral absence of the vas deferens (CBAVD) (PMIDs: 7691344 (1993), 15776432 (2005), 17329263 (2007), 23891399 (2014)). In addition, in vitro functional analyses report this variant results in decreased chloride transport and maturation, and defective CFTR processing (PMID: 23974870 (2013), and 23891399 (2014)). Therefore, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jul 18, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

CFTR-related disorder Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Apr 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 26, 2024	The CFTR c.617T>G variant is predicted to result in the amino acid substitution p.Leu206Trp. This variant has been reported to be causative for cystic fibrosis (see, for example, Chain et al. 2005. PubMed ID: 15776432; Sosnay et al. 2013. PubMed ID: 23974870). This variant is classified as pathogenic by multiple independent submitters to the ClinVar database, and has been reviewed by an expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/7190/). This variant is reported in 0.054% of alleles in individuals of Latino descent in gnomAD. In summary, we classify this variant as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Cystic fibrosis;na:CFTR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 05, 2022

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 30, 2023

- -

ivacaftor response - Efficacy Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	28
Dann	Benign	0.96
DEOGEN2	Pathogenic	0.92	D;.;.;D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.8	M;.;.;.;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.2	D;.;.;D;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.98
MVP		1.0
MPC		0.013
ClinPred		0.38	T
GERP RS		5.5
Varity_R		0.83
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs121908752; hg19: chr7-117175339;