Total submissions: 15
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, |
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 |
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, |
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- |
RCV000757856 | SCV001822011 | likely pathogenic | Cystic fibrosis | 2021-07-22 | criteria provided, single submitter | clinical testing | |
Genome Diagnostics Laboratory, |
RCV000757856 | SCV002507339 | likely pathogenic | Cystic fibrosis | 2020-03-30 | criteria provided, single submitter | clinical testing | |
CFTR- |
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. |
Gene |
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, |
RCV000587145 | SCV004226571 | pathogenic | not provided | 2022-08-03 | criteria provided, single submitter | clinical testing | PP3, PM3_strong, PS3 |
Genome Diagnostics Laboratory, |
RCV002232555 | SCV002507423 | likely pathogenic | CFTR-related disorders | 2020-03-30 | no assertion criteria provided | clinical testing |