Submissions for variant NM_000492.4(CFTR):c.3154T>G (p.Phe1052Val)

gnomAD frequency: 0.00039  dbSNP: rs150212784

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV000660777	SCV000783016	drug response	ivacaftor response - Efficacy	2021-03-24	reviewed by expert panel	curation	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046799	SCV000052171	likely pathogenic	Cystic fibrosis	2023-03-01	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3154T>G (p.Phe1052Val) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 250362 control chromosomes in the gnomAD database, including one homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (0.00065 vs 0.013), allowing no conclusion about variant significance. c.3154T>G has been reported in the literature in individuals affected with Cystic Fibrosis, both in homozygous patients (e.g. Lakeman_2008) and in compound heterozygosity with other known pathogenic mutations (e.g. Brancolini_1995, Onay_1998, Sobczynska-Tomaszewska_2013, Levy_2019). These data indicate that the variant is likely to be associated with disease, however no cosegregation studies are reported in the literature. In addition,the variant has frequently been associated with non-classical manifestations of disease such as pancreatic sufficiency (e.g. Brancolini_1995) and borderline or normal sweat chloride levels (e.g. Hirtz_2004, Basaran_2017), and was found in compound heterozygosity with a known pathogenic mutation in several patients who were asymptomatic at the time of testing (e.g. Boyne_2000, Grangeia_2018). These data strongly suggest that this variant is a "mild" mutation with varying clinical consequences. The variant has also been detected in individuals with other CFTR-related disorders such as CBAVD (Congenital Bilateral Absence of Vas Deferens; e.g. Mercier_1995) and pancreatitis (e.g. Tzetis_2007, Pelletier_2010). In addition the variant has been found in several patients with other lung diseases such as rheumatoid-associated bronchiectasis (e.g. Puechal_2011) and COPD (e.g. Divac_2004) without strong evidence for causality. Several publications report experimental evidence evaluating an impact on protein function. In vitro experiments indicated that the variant mildly affects chloride channel function (Sosnay_2013, Van Goor_2014). In addition, this variant was found to alter the regulation and gating properties of chloride channels, though cAMP-stimulated efflux of chlorine channel was normal (Seibert_1996, Cotton_1996). Twenty clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant VUS (n=7), likely pathogenic (n=7) and pathogenic (n=6). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000046799	SCV000074812	uncertain significance	Cystic fibrosis	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1052 of the CFTR protein (p.Phe1052Val). This variant is present in population databases (rs150212784, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been reported in individuals affected with cystic fibrosis, congenital absence of the vas deferens, pancreatitis, pancreatic cancer, and bronchiectasis (PMID: 9239681, 20460946, 18373402, 12439892, 17489851, 19885835, 12843327). However, this variant has also been reported to co-occur with p.Phe508del in at least one asymptomatic individual with borderline sweat chloride levels (PMID: 24204751) and with mild pathogenic variants in individuals with normal sweat chloride tests (PMID: 19885835, 11883825, 10801389, 19318035). ClinVar contains an entry for this variant (Variation ID: 35865). 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 in cultured cells have shown that CFTR protein with this missense variant retains ~87% of chloride transport activity relative to wild-type protein (PMID: 23891399, 26823392, 23974870). By comparison, most severe pathogenic variants, such as p.Phe508del, exhibit ~0-1% transport activity in these same assays. The clinical impact of this small effect on protein function is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224816	SCV000280878	pathogenic	not provided	2015-03-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000224816	SCV000601088	likely pathogenic	not provided	2023-05-03	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported as homozygous (PMIDs: 12439892 (2002) and 18373402 (2008)) or compound heterozygous in individuals with cystic fibrosis (PMIDs: 9521595 (1998), 12200467 (2002), 15480987 (2004), 29168366 (2017), and 36458240 (2022)) as well as in CFTR-related disorders (PMIDs: 7544319 (1995), 10970190 (2000), 19885835 (2010), 24204751 (2013), and 32150665 (2020)). In addition, functional studies indicate this variant has neutral effect on CFTR protein processing and chloride channel conductance but reduced certain gating and kinetic properties of the chloride channels (PMIDs: 8702904 (1996), 8662892 (1996), and 23891399 (2014)). The frequency of this variant in the general population, 0.006 (16/2664 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic.
Eurofins Ntd Llc (ga)	RCV000224816	SCV000700272	uncertain significance	not provided	2018-07-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224816	SCV000883565	pathogenic	not provided	2023-03-21	criteria provided, single submitter	clinical testing	The CFTR c.3154T>G; p.Phe1052Val variant (rs150212784) has been reported in patients diagnosed with cystic fibrosis (Brancolini 1995, Lakeman 2008, Mercier 1993, Onay 1998, Sosnay 2013) and CFTR-related disorders (Gallati 2009, Pelletier 2010, Puechal 2011, Tzetis 2007), and associated with varying clinical consequences (CFTR2 database). Functional studies indicate that the variant protein has normal maturation and conductance (Sosnay 2013, Van Goor 2014), but altered channel kinetics (Cotten 1996, Seibert 1996). The variant is reported in ClinVar (Variation ID: 35865). It is found in the general population with an overall allele frequency of 0.06% (177/281760 alleles, including 1 homozygote) in the Genome Aggregation Database. The phenylalanine at codon 1052 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.948). Based on available information, this variant is considered to be pathogenic with a variable presentation of clinical phenotypes. References: CFTR2 database: http://cftr2.org/ Brancolini V et al. Search for mutations in pancreatic sufficient cystic fibrosis Italian patients: detection of 90% of molecular defects and identification of three novel mutations. Hum Genet. 1995; 96(3):312-8. Cotten J et al. Effect of cystic fibrosis-associated mutations in the fourth intracellular loop of cystic fibrosis transmembrane conductance regulator. J Biol Chem. 1996; 271(35):21279-84. Gallati S et al Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009; 19(5):685-94. Lakeman P et al. CFTR mutations in Turkish and North African cystic fibrosis patients in Europe: implications for screening. Genet Test. 2008;12(1):25-35. Mercier B et al. Identification of eight novel mutations in a collaborative analysis of a part of the second transmembrane domain of the CFTR gene. Genomics. 1993; 16(1):296-7. Onay T et al. Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I). Hum Genet. 1998; 102(2):224-30. Pelletier A et al. CFTR gene mutation in patients with apparently idiopathic pancreatitis: lack of phenotype-genotype correlation. Pancreatology. 2010; 10(2-3):158-64. Puechal X et al. Mutations of the cystic fibrosis gene in patients with bronchiectasis associated with rheumatoid arthritis. Ann Rheum Dis. 2011; 70(4):653-9. Seibert F et al. Disease-associated mutations in the fourth cytoplasmic loop of cystic fibrosis transmembrane conductance regulator compromise biosynthetic processing and chloride channel activity. J Biol Chem. 1996; 271(25):15139-45. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. Tzetis M et al. Contribution of the CFTR gene, the pancreatic secretory trypsin inhibitor gene (SPINK1) and the cationic trypsinogen gene (PRSS1) to the etiology of recurrent pancreatitis. Clin Genet. 2007; 71(5):451-7. 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.
Mendelics	RCV000046799	SCV000886354	uncertain significance	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000770985	SCV000897972	uncertain significance	Hereditary pancreatitis	2018-04-27	criteria provided, single submitter	clinical testing	This recessive variant was identified in a patient with repetitive pancreatitis. The patient harbours also a second variant (see above) in this gene in compound heterozygosity
Johns Hopkins Genomics, Johns Hopkins University	RCV000046799	SCV000992329	likely pathogenic	Cystic fibrosis	2019-03-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004295	SCV001163171	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV001009471	SCV001169566	pathogenic	CFTR-related disorders	2018-03-26	criteria provided, single submitter	curation
Ambry Genetics	RCV000046799	SCV001180126	pathogenic	Cystic fibrosis	2022-01-19	criteria provided, single submitter	clinical testing	The p.F1052V pathogenic mutation (also known as c.3154T>G), located in coding exon 20 of the CFTR gene, results from a T to G substitution at nucleotide position 3154. The phenylalanine at codon 1052 is replaced by valine, an amino acid with highly similar properties. The p.F1052V alteration has been reported as a variant of varying clinical consequences (VVCC) and has been identified in trans with a pathogenic mutation in individuals with intermediate or normal sweat chloride levels, pancreatic sufficiency, and negative for Pseudomonas infection (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Salinas DB et al. PLoS ONE, 2016 May;11:e0155624; Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98). It has also been reported in the homozygous state and in trans with a pathogenic mutation in individuals with cystic fibrosis (Onay T et al. Hum. Genet., 1998 Feb;102:224-30; Lakeman P et al. Genet. Test., 2008 Mar;12:25-35). In vitro studies demonstrated that the p.F1052V mutant protein is able to mature normally but has reduced activity compared to wild-type (Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000046799	SCV001251678	likely pathogenic	Cystic fibrosis	2020-05-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224816	SCV001501421	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	CFTR: PM1:Strong, PM3:Strong, PS3:Moderate, PM2:Supporting, PP3
Mayo Clinic Laboratories, Mayo Clinic	RCV000224816	SCV001714244	uncertain significance	not provided	2019-12-17	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000046799	SCV001781360	likely pathogenic	Cystic fibrosis	2021-07-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000224816	SCV001872928	uncertain significance	not provided	2022-12-02	criteria provided, single submitter	clinical testing	Published functional studies suggest regulation and gating of the channel is affected, however, chloride conductance capabilities are similar to wildtype (Cotten et al., 1996; Seibert et al., 1996; Sosnay et al., 2013); Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in apparent homozygous state or with a pathogenic CFTR variant in individuals with cystic fibrosis (CF) and CFTR-related disorders but also in individuals with no reported features of CF (Brancolini et al., 1995; Kilinc et al., 2002; Lakeman et al., 2008; Wine et al., 2013; Salinas et al., 2016; Basaran et al., 2017; Grangeia et al., 2018; Zapolnik et al., 2020; Erdogan et al., 2021); This variant is associated with the following publications: (PMID: 25033378, 25087612, 26437683, 31759907, 30938940, 21131649, 23974870, 20460946, 20021716, 23891399, 24204751, 26823392, 25704068, 29292091, 29805046, 9239681, 18373402, 17489851, 19885835, 12843327, 11883825, 10801389, 15463907, 7683628, 29589582, 29168366, 19318035, 12439892, 9521595, 27214204, 31331863, 32003480, 31005549, 32003094, 30561903, 32357917, 30146269, 32113160, 32773111, 32819855, 33393655, 32926152, 33470563, 32484936, 34426522, 34756682, 34949556, 8662892, 8702904, 28408918, 34413153, 34996830, 34797250, 30540547, Turkyilmaz[CaseReport]2021, Oraimi[CaseReport]2022, 34860163, 22892530, 7544319)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000046799	SCV002507386	uncertain significance	Cystic fibrosis	2021-03-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000770985	SCV002529711	likely pathogenic	Hereditary pancreatitis	2021-04-29	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000770985	SCV002580737	pathogenic	Hereditary pancreatitis	2022-02-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473140	SCV004211621	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-10-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000224816	SCV001553295	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CFTR p.Phe1052Val variant was identified in 7 of 2126 proband chromosomes (frequency: 0.003) from individuals or families with cystic fibrosis (CF) or pancreatitis and was identified in 4 of 422 control chromosomes (frequency: 0.009) (Tzets_2007_PMID: 17489851; Grangeia_2018_PMID: 29589582; Pelletier_2010_PMID: 20460946). The variant was also identified in dbSNP (ID: rs150212784), ClinVar (classified as a VUS by five submitters, likely pathogenic by two submitters and as pathogenic by two submitters) and LOVD 3.0; the variant was not identified in Cosmic. The variant was also identified in control databases in 177 of 281760 chromosomes (1 homozygous) at a frequency of 0.000628 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 21 of 10348 chromosomes (freq: 0.002029), Other in 9 of 7174 chromosomes (freq: 0.001255), European (non-Finnish) in 117 of 128594 chromosomes (freq: 0.00091), Latino in 22 of 35218 chromosomes (freq: 0.000625), European (Finnish) in 6 of 25038 chromosomes (freq: 0.00024) and South Asian in 2 of 30532 chromosomes (freq: 0.000066), while the variant was not observed in the African and East Asian populations. The F1052V variant was identified in a Portuguese child who also carried the classic deltaF508 variant, however this child was not affected with CF (Grangeia_2018_PMID: 29589582). The F1052V and deltaF508 variants have also been reported in the compound heterozygous state in a patient with pancreatic cancer, however this individual was not affected with CF; this suggest that the F1052V variant may not be causal of CF (McWilliams_2010_PMID: 19885835). The p.Phe1052 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001009471	SCV002507472	likely pathogenic	CFTR-related disorders	2021-03-30	no assertion criteria provided	clinical testing