7-117611595-T-G
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP5_Strong
The NM_000492.4(CFTR):c.3154T>G(p.Phe1052Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000464 in 1,608,938 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as drug response (★★★).
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.3154T>G | p.Phe1052Val | missense_variant | Exon 20 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.000381 AC: 58AN: 152114Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000647 AC: 162AN: 250362Hom.: 1 AF XY: 0.000695 AC XY: 94AN XY: 135322
GnomAD4 exome AF: 0.000472 AC: 688AN: 1456824Hom.: 1 Cov.: 30 AF XY: 0.000488 AC XY: 354AN XY: 725064
GnomAD4 genome 0.000381 AC: 58AN: 152114Hom.: 0 Cov.: 31 AF XY: 0.000363 AC XY: 27AN XY: 74302
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:8Uncertain:3
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. Four of four 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 1 homozygotes. This frequency is not significantly higher than estimated 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, Bihler_2024). 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). The following publications have been ascertained in the context of this evaluation (PMID: 29168366, 38388235, 10970190, 7544319, 28603918, 8702904, 9239681, 15463907, 28408918, 20021716, 7536669, 10801389, 29589582, 15480987, 9620832, 12439892, 25033378, 18373402, 30540547, 19885835, 7529962, 7683628, 9521595, 11883825, 20460946, 21131649, 23523379, 19318035, 8662892, 22892530, 23974870, 32150665, 26436105, 1284534, 17489851, 11354633, 23891399, 12200467). ClinVar contains an entry for this variant (Variation ID: 35865). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
The p.F1052V variant (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. This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 02/28/2024). This variant has also been identified in the homozygous state and in trans/likely in trans with another CFTR variant in individuals with a wide range of clinical manifestations, including asymptomatic patients as well as those with cystic fibrosis or CFTR-related disorder (Kanavakis E et al. Mol Hum Reprod, 1998 Apr;4:333-7; Onay T et al. Hum Genet, 1998 Feb;102:224-30; Padoan R et al. Acta Paediatr, 2002;91:82-7; Lakeman P et al. Genet. Test., 2008 Mar;12:25-35; Claustres M et al. Hum Mutat, 2017 Oct;38:1297-1315; Terlizzi V et al. Pediatr Pulmonol, 2020 May;55:1089-1093; Hatton A et al. J Cyst Fibros, 2022 May;21:448-455). In vitro studies demonstrated that this variant does not impact maturation of CFTR protein, but reduces CFTR function (Cotten JF et al. J. Biol. Chem., 1996 Aug;271:21279-84; Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45; Sosnay PR et al. Nat Genet, 2013 Oct;45:1160-7; Van Goor F et al. J Cyst Fibros, 2014 Jan;13:29-36). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, this variant is unlikely to be causative of classic cystic fibrosis; however, it likely contributes to the development of a CFTR-related disorder. This alteration is thus classified as likely pathogenic. -
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not provided Pathogenic:4Uncertain:4
Published functional studies suggest regulation and gating of the channel is affected, however, chloride conductance capabilities are similar to wildtype (PMID: 8702904, 8662892, 23974870); 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 (PMID: 7544319, 12439892, 18373402, 24204751, 29168366, 29589582, 33393655, 34860163, 27214204); 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; This variant is associated with the following publications: (PMID: 25033378, 25087612, 26437683, 36207272, 31759907, 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, 31005549, 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, 37046605, 30938940, 36458240, 35418593, 35997436, 36650664, 32003094, 37823318, 34405919, 38493004, 37628659, 38203285, 38392563, 38744964, 38515211, 32003480, 36409994, 38388235) -
The c.3154T>G (p.Phe1052Val) variant (also known as F1052V) has been reported in the published literature as homozygous (PMIDs: 12439892 (2002), 18373402 (2008)) or compound heterozygous in individuals affected with cystic fibrosis (PMIDs: 9521595 (1998), 12200467 (2002), 15480987 (2004), 29168366 (2017), 36458240 (2022)), as well as in CFTR-related disorders (PMIDs: 7544319 (1995), 10970190 (2000), 19885835 (2010), 24204751 (2013), 32150665 (2020)). In addition, functional studies indicated that this variant did not hinder CFTR protein processing and chloride channel conductance, but it did reduce certain gating and kinetic properties of the chloride channel (PMIDs: 8702904 (1996), 8662892 (1996), 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. -
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. -
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CFTR: PM1:Strong, PM3:Strong, PS3:Moderate, PM2:Supporting, PP3 -
CFTR-related disorder Pathogenic:2Uncertain:1
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The CFTR c.3154T>G variant is predicted to result in the amino acid substitution p.Phe1052Val. This variant has been reported in 33 patients with cystic fibrosis and an average sweat chloride level of 47mEq/L (www.cftr2.org). Functional studies indicated that the p.Phe1052Val variant did not alter CFTR chloride channel conductance or expression in cell lines (see supplement table 2 in Sosnay et al. 2013. PubMed ID: 23974870; Van Goor et al. 2014. PubMed ID: 23891399). This variant has been reported in individuals affected with suspected cystic fibrosis (see for example: Basaran et al. 2017. PubMed ID: 29168366; Kilinc et al. 2002. PubMed ID: 12439892; Lakeman et al. 2008. PubMed ID: 18373402; Vrettou et al. 2002. PubMed ID: 12200467), but has also been published as a heterozygous variant in the absence of a second possible causative variant, and/or in patients with limited clinical or genetic evidence to support pathogenicity (see for example: Divac et al. 2004. PubMed ID: 15463907; Tzetis et al. 2001. PubMed ID: 11354633; Kilinc et al. 2002. PubMed ID: 12439892; McWilliams et al. 2010. PubMed ID: 19885835; Grangeia et al. 2018. PubMed ID: 29589582). This variant is reported in 0.20% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including 1 homozygote. In ClinVar, this variant has been interpreted as uncertain, likely pathogenic, or pathogenic by outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/35865/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
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Hereditary pancreatitis Pathogenic:2Uncertain:1
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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 -
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:2
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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. -
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
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Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
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ivacaftor response - Efficacy Other:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at