Submissions for variant NM_000492.4(CFTR):c.571T>G (p.Phe191Val)

gnomAD frequency: 0.00007  dbSNP: rs141482808

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000757856	SCV001981562	pathogenic	Cystic fibrosis	2020-01-10	reviewed by expert panel	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000757856	SCV000697035	pathogenic	Cystic fibrosis	2024-11-25	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.571T>G (p.Phe191Val) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Four 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 250352 control chromosomes. c.571T>G has been reported in the literature in individuals with features of cystic fibrosis in the presumed compound heterozygous state with other pathogenic variants (e.g. Groman_2002, Krasnov_2008, McCravy_2020, Gonska_2021, Cornet_2023). It has also been reported as a homozygous genotype in an African-American infant diagnosed with Cystic Fibrosis by newborn screening (NBS) (Giusti_2008). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function suggests the variant disrupts expression of the mature protein and ion transport, which can be corrected by drug treatment and results in approximately 4.58% of normal chloride channel conductance relative to wild type (McCravy_2020, Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 36751320, 18500736, 34814176, 12167682, 18951463, 32265312, 31845523, 35527187, 34583889, 26708955). ClinVar contains an entry for this variant (Variation ID: 495953). Based on the evidence outlined above, the variant was classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000587145	SCV000700410	likely pathogenic	not provided	2017-04-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000757856	SCV000886367	pathogenic	Cystic fibrosis	2022-05-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002123	SCV001159974	likely pathogenic	not specified	2019-02-21	criteria provided, single submitter	clinical testing	The CFTR c.571T>G; p.Phe191Val variant (rs141482808) is reported in the literature in individuals affected with cystic fibrosis (CF) or nonclassic CF (Giusti 2008, Groman 2002, Schrijver 2016). This variant has been observed in the homozygous state in a newborn with a positive sweat chloride test (Giusti 2008) and in an individual with nonclassic CF that carried an additional pathogenic CFTR variant (Groman 2002). Similarly, in testing performed at ARUP Laboratories, the p.Phe191Val variant has been observed in an individual with elevated sweat chloride that carried a second pathogenic variant. The p.Phe191Val variant is found on only three chromosomes (3/16210 alleles, 0.02%) in the African population in the Genome Aggregation Database, indicating it is not a common polymorphism. The phenylalanine at codon 191 is moderately conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. However, based on available information, including its incidence in affected individuals, this variant is considered to be likely pathogenic. References: Giusti R et al. Elevated IRT levels in African-American infants: implications for newborn screening in an ethnically diverse population. Pediatr Pulmonol. 2008 Jul;43(7):638-41. Groman JD et al. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med. 2002 Aug 8;347(6):401-7. Schrijver I et al. The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing. J Mol Diagn. 2016 Jan;18(1):39-50.
Baylor Genetics	RCV001004436	SCV001163481	likely pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000757856	SCV001209861	uncertain significance	Cystic fibrosis	2021-12-12	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 191 of the CFTR protein (p.Phe191Val). This variant is present in population databases (rs141482808, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 12167682, 18500736, 26708955). ClinVar contains an entry for this variant (Variation ID: 495953). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Genome-Nilou Lab	RCV000757856	SCV001822011	likely pathogenic	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000757856	SCV002507339	likely pathogenic	Cystic fibrosis	2020-03-30	criteria provided, single submitter	clinical testing
CFTR-France	RCV002281577	SCV002570007	pathogenic	Cystic fibrosis; CFTR-related disorder	2021-01-18	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
Ambry Genetics	RCV000757856	SCV002649637	likely pathogenic	Cystic fibrosis	2025-02-13	criteria provided, single submitter	clinical testing	The p.F191V variant (also known as c.571T>G), located in coding exon 5 of the CFTR gene, results from a T to G substitution at nucleotide position 571. The phenylalanine at codon 191 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with non-classic cystic fibrosis in conjunction with other pathogenic mutations; however, the phase of these alterations was not provided (Groman JD et al. N. Engl. J. Med., 2002 Aug;347:401-7; McCravy MS et al. Eur Respir J, 2020 Jul;56:). This variant was also identified in the homozygous state in an African American newborn with cystic fibrosis and elevated sweat chloride levels (Giusti R et al. Pediatr. Pulmonol., 2008 Jul;43:638-41). 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 02/13/2025). This variant has <10% of wild type quantity and function in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 02/13/2025). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000587145	SCV003915092	likely pathogenic	not provided	2023-04-06	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect: decreased protein expression and reduced channel activity (McCravy 2020); 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: 12167682, 26708955, 31845523, 32265312, 18951463, 34996830, 35527187, 34583889, 35451201, 36751320, 18500736)
Baylor Genetics	RCV003471942	SCV004213279	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-17	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000587145	SCV004226571	pathogenic	not provided	2022-08-03	criteria provided, single submitter	clinical testing	PP3, PM3_strong, PS3
Fulgent Genetics, Fulgent Genetics	RCV005034155	SCV005673285	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-04-13	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002232555	SCV002507423	likely pathogenic	CFTR-related disorder	2020-03-30	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV002232555	SCV005346812	pathogenic	CFTR-related disorder	2024-03-07	no assertion criteria provided	clinical testing	The CFTR c.571T>G variant is predicted to result in the amino acid substitution p.Phe191Val. This variant has been reported in individuals with classic and non-classic cystic fibrosis (Groman et al. 2002. PubMed ID: 12167682; Schrijver et al. 2016. PubMed ID: 26708955; Gunnett et al. 2023. PubMed ID: 36969284). Additionally, this variant has been reported compound heterozygous with another pathogenic variant in a patient with cystic fibrosis (Cornet et al. 2022. PubMed ID: 36751320). In vitro, and in vivo functional and biochemical studies using human nasal epithelial cells demonstrated diminished protein expression and reduced ion transport which improved with combination therapy treatment (McCravy et al. 2020. PubMed ID: 32265312). This variant is reported in 0.019% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.