Submissions for variant NM_000492.4(CFTR):c.2930C>T (p.Ser977Phe)

gnomAD frequency: 0.00001  dbSNP: rs141033578

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV000660775	SCV000783014	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811323	SCV000883568	likely pathogenic	not provided	2021-09-27	criteria provided, single submitter	clinical testing	The CFTR c.2930C>T, p.Ser977Phe variant (rs141033578) has been reported in patients diagnosed with cystic fibrosis (Le Marechal 2001, Loumi 2008, Scotet 2003, Lakeman 2008) and CFTR-related disorders (Bareil 2007, Goubau 2009, Lebecque 2002, Ratbi 2007, Sermet-Gaudelus 2010, Sorio 2013, Trujillano 2013, Tzetis 2001). It was identified in-cis with the pathogenic 12TG-5T variant in multiple individuals (Lebecque 2002, Sorio 2013, Trujillano 2013, Tzetis 2001); therefore, it is possible that p.Ser977Phe and 12TG-5T could represent a complex allele if found together. Functional characterization of the p.Ser977Phe variant indicates wildtype levels of CFTR expression and protein maturation, but the variant protein has a chloride transport activity at 5 percent of wildtype CFTR (Van Goor 2014, CFTR2 database). The variant is listed in ClinVar (Variation ID: 53601), and found in the general population with an overall allele frequency of 0.001% (3/251114 alleles) in the Genome Aggregation Database. The serine at codon 977 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.906). Due to the variability of associated clinical phenotype, the p.Ser977Phe variant is considered to be likely pathogenic with varying clinical consequences. References: CFTR2 database: http://cftr2.org/ Bareil C et al. Comprehensive and rapid genotyping of mutations and haplotypes in congenital bilateral absence of the vas deferens and other cystic fibrosis transmembrane conductance regulator-related disorders. J Mol Diagn. 2007 Nov;9(5):582-8. PMID: 17975025. Goubau C et al. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax. 2009 Aug;64(8):683-91. PMID: 19318346. Lakeman P et al. CFTR mutations in Turkish and North African cystic fibrosis patients in Europe: implications for screening. Genet Test. 2008 Mar;12(1):25-35. PMID: 18373402. Le Marechal C et al. Complete and rapid scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by denaturing high-performance liquid chromatography (D-HPLC): major implications for genetic counselling. Hum Genet. 2001; 108(4):290-8. PMID: 11379874. Lebecque P et al. Mutations of the cystic fibrosis gene and intermediate sweat chloride levels in children. Am J Respir Crit Care Med. 2002; 165(6):757-61. PMID: 11897640. Loumi O et al. CFTR mutations in the Algerian population. J Cyst Fibros. 2008 Jan;7(1):54-9. PMID: 17572159. Ratbi I et al. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod. 2007; 22(5):1285-91. PMID: 17329263. Scotet V et al. Comparison of the CFTR mutation spectrum in three cohorts of patients of Celtic origin from Brittany (France) and Ireland. Hum Mutat. 2003 Jul;22(1):105. PMID: 12815607. Sermet-Gaudelus I et al. Clinical phenotype and genotype of children with borderline sweat test and abnormal nasal epithelial chloride transport. Am J Respir Crit Care Med. 2010 Oct 1;182(7):929-36. PMID: 20538955. Sorio C et al. Impaired CFTR function in mild cystic fibrosis associated with the S977F/T5TG12complex allele in trans with F508del mutation. J Cyst Fibros. 2013; 12(6):821-5. PMID: 23361109. 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. PMID: 23974870 Trujillano D et al. Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR. J Med Genet. 2013; 50(7):455-62. PMID: 23687349. Tzetis M et al. CFTR gene mutations--including three novel nucleotide substitutions--and haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease. Hum Genet. 2001; 108(3):216-21. PMID: 11354633. 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. PMID: 23891399.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577087	SCV000917206	pathogenic	Cystic fibrosis	2023-08-24	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2930C>T (p.Ser977Phe) 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 251218 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2930C>T has been reported in the literature as a variant of varying clinical consequence due to reports of its presence in individuals affected with Non-classic Cystic Fibrosis, CBAVD, ICP, and classic CF (example, Bareil_2007, Claustres_2000, Goubau_2009, Lakeman_2008, Loumi_2008, Ratbi_2007, Scotet_2003, Sermet-Gaudelus_2010, Sofia_2016, Sorio_2013, Sosnay_2013, Terlizzi_2016, Tzetis_2001, Sasaki_2020, Sawicki_2022). At least five of these patients were found to also harbor the F508del variant (e.g., Sermet-Gaudelus_2010, Sawicki_2022). Additionally, in some of these reports the variant was reported in cis with the 5T allele (example, Bareil_2007, Sorio_2013, Terlizzi_2016). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence finding that the variant results in a defect in protein function (e.g., Van Goor_2014, Bihler_2023 (no PMID)). The most pronounced variant effect results in decreased chloride ion transport (5.5% of wild-type) and decreased CFTR maturation (37% of wild-type) in a Fischer rat thyroid (FRT) cell system (Van Goor_2014). The following publications have been ascertained in the context of this evaluation (PMID: 17975025, 10923036, 26014425, 19318346, 18373402, 17572159, 25910067, 32934006, 25735457, 17329263, 12815607, 20538955, 27264265, 23361109, 23974870, 27738188, 11354633, 23891399, 32483343, 36319933). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n = 4) or likely pathogenic (n = 2). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001004491	SCV001163536	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV001009389	SCV001169242	pathogenic	Cystic fibrosis; CFTR-related disorder	2018-01-29	criteria provided, single submitter	curation	when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577087	SCV001578434	pathogenic	Cystic fibrosis	2024-02-25	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 977 of the CFTR protein (p.Ser977Phe). This variant is present in population databases (rs141033578, gnomAD 0.01%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 19318346, 23361109). 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: 53601). 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: 23891399). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000577087	SCV002507328	likely pathogenic	Cystic fibrosis	2019-06-27	criteria provided, single submitter	clinical testing
Mendelics	RCV002247436	SCV002518683	pathogenic	Hereditary pancreatitis	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000577087	SCV002752405	pathogenic	Cystic fibrosis	2019-01-11	criteria provided, single submitter	clinical testing	The p.S977F pathogenic mutation (also known as c.2930C>T), located in coding exon 18 of the CFTR gene, results from a C to T substitution at nucleotide position 2930. The serine at codon 977 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. This alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed January 11, 2019). It has been reported in cis with (TG)12-5T and in trans with a second CFTR alteration in individuals with varying clinical phenotypes including cystic fibrosis, congenital bilateral absences of the vas deferens (CBAVD), other CFTR-related disorders, and an asymptomatic carrier (Claustres M et al. Hum. Mutat., 2017 10;38:1297-1315). In one study, this mutation was confirmed in cis with (TG)12-5T and in trans with p.F508del in a male with azoospermia, bilateral bronchiectasis, acute pancreatitis, recurrent lung infections, sweat chloride levels of 40 and 42 mmol/L, and normal lung function (Sorio C et al. J. Cyst. Fibros., 2013 Dec;12:821-5). In FRT cells, levels of mature CFTR protein and chloride transport were reduced compared to wild type (Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003474558	SCV004213458	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031503	SCV005666394	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-03-26	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577087	SCV000679033	not provided	Cystic fibrosis		no assertion provided	literature only
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002228325	SCV002507412	likely pathogenic	CFTR-related disorder	2019-06-27	no assertion criteria provided	clinical testing