Submissions for variant NM_000492.4(CFTR):c.3353C>T (p.Ser1118Phe)

dbSNP: rs146521846

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000577360	SCV000924222	pathogenic	Cystic fibrosis	2017-12-08	reviewed by expert panel	research
Revvity Omics, Revvity	RCV001781376	SCV002022527	likely pathogenic	not provided	2022-09-23	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000577360	SCV002053737	pathogenic	Cystic fibrosis		criteria provided, single submitter	clinical testing
CFTR-France	RCV002281551	SCV002570010	pathogenic	Cystic fibrosis; CFTR-related disorder	2019-07-17	criteria provided, single submitter	curation	the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577360	SCV002600724	pathogenic	Cystic fibrosis	2022-10-26	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3353C>T (p.Ser1118Phe) 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 1.2e-05 in 250416 control chromosomes. c.3353C>T has been reported in the literature as a biallelic compound heterozygous genotype in multiple individuals affected with Cystic Fibrosis (example, McCague_2019, Penmatsa_2009). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (example, Han_2018, Penmatsa_2009). The most pronounced variant effect results in <10% of normal CFTR residual function (Han_2018) and impaired maturation (Penmatsa_2009). One clinical diagnostic laboratory, an expert panel (CFTR-2) and a database (CFTR-France) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000577360	SCV002606746	pathogenic	Cystic fibrosis	2021-05-22	criteria provided, single submitter	clinical testing	The p.S1118F pathogenic mutation (also known as c.3353C>T and c.3485C>T), located in coding exon 20 of the CFTR gene, results from a C to T substitution at nucleotide position 3353. The serine at codon 1118 is replaced by phenylalanine, an amino acid with highly dissimilar properties. The mutation was described in trans with p.F508del in a newborn who presented with meconium ileus, pancreatic sufficiency and indeterminate sweat chloride levels (Penmatsa et al. Pediatr. Pulmonol. 2009;44(10):1003-9), and has been detected in trans with a pathogenic mutation in CFTR by our laboratory (Ambry internal data). Several in vitro studies have suggested this mutation, which is located in transmembrane 11 domain, decreases the chloride channel voltage, gating, permeability and efficiency, and results in reduced function compared to wild type (Zhang et al. Biophys. J. 2000;79(1):298-313; Penmatsa et al Pediatr. Pulmonol. 2009;44(10):1003-9; Raraigh KS et al. Am J Hum Genet. 2018 06;102(6):1062-1077). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577360	SCV002929527	likely pathogenic	Cystic fibrosis	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1118 of the CFTR protein (p.Ser1118Phe). This variant is present in population databases (rs146521846, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of CFTR-related conditions (PMID: 19774621, 23276700, 34782259). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53722). 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 have shown that this missense change affects CFTR function (PMID: 10866956, 19774621, 29805046, 30046002). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Lifecell International Pvt. Ltd	RCV000577360	SCV003923320	pathogenic	Cystic fibrosis		criteria provided, single submitter	clinical testing	A Homozygote Missense variant c.3353C>T in Exon 20 of the CFTR gene that results in the amino acid substitution p.Ser1118Phe was identified. The observed variant has a minor allele frequency of 0.00001/% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (variant ID 53722). In vitro studies have suggested this mutation, which is located in transmembrane 11 domain, decreases the chloride channel voltage, gating, permeability and efficiency, and results in reduced function compared to wild type (Planells-Cases R et al., 2000). This variant has been observed in many individuals affected with cystic fibrosis reported by (McCague AF, et al., 2019).Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Baylor Genetics	RCV003474577	SCV004213261	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-01-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031511	SCV005666412	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-06-24	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577360	SCV000679375	not provided	Cystic fibrosis		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004734608	SCV005348884	likely pathogenic	CFTR-related disorder	2024-09-13	no assertion criteria provided	clinical testing	The CFTR c.3353C>T variant is predicted to result in the amino acid substitution p.Ser1118Phe. This variant has been reported in the compound heterozygous state (with the p.Phe508del variant) in an individual with atypical cystic fibrosis symptoms with intermediate sweat chloride level (Penmatsa et al. 2009. PubMed ID: 19774621). This variant has also been reported in the compound heterozygous state (with the p.Cys343* variant) in an individual with cystic fibrosis presenting pseudo-Bartter's syndrome (Nayak et al. 2018. doi: 10.7199/ped.oncall.2018.47). Functional studies show the p.Ser1118Phe substitution impacts normal protein function (Zhang et al. 2000. PubMed ID: 10866956; Penmatsa et al. 2009. PubMed ID: 19774621; Raraigh et al. 2018. PubMed ID: 29805046). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and is interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/53722/). This variant is interpreted as likely pathogenic.