ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs141482808
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Total submissions: 15
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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 likely pathogenic Cystic fibrosis 2023-11-09 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 (gnomAD). 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). The variant continues to be cited by others in relation to the presence of FDA-approved treatments and its presence as a CF-causing variant in the CFTR2 database (e.g. Raraigh_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, suggesting the variant disrupts expression of the mature protein and ion transport, which can be corrected by drug treatment (McCravy_2020). The following publications have been ascertained in the context of this evaluation (PMID: 12167682, 18951463, 18500736, 26708955, 31845523, 34583889, 35527187, 34814176, 36751320, 32265312). Ten submitters, including an expert panel, have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=3, including a CFTR2 expert panel), likely pathogenic (n=6), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely 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
Invitae 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 disorders 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 2023-07-18 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 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 2023-10-22 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
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002232555 SCV002507423 likely pathogenic CFTR-related disorders 2020-03-30 no assertion criteria provided clinical testing

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