ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.571T>G (p.Phe191Val) (rs141482808)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000587145 SCV000697035 uncertain significance not provided 2016-08-09 criteria provided, single submitter clinical testing Variant summary: The CFTR c.571T>G (p.Phe191Val) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/118270 control chromosomes at a frequency of 0.0000085, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant has been reported in multiple affected individuals including one non-classic CF patient (Groman_2002) and CF patients without clinical information (Schrijver_2016). The variant of interest has not, to our knowledge, been reported via clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as VUS-possibly pathogenic until more information becomes available.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587145 SCV000700410 likely pathogenic not provided 2017-04-21 criteria provided, single submitter clinical testing
Mendelics RCV000757856 SCV000886367 uncertain significance Cystic fibrosis 2018-11-05 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 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with valine at codon 191 of the CFTR protein (p.Phe191Val). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and valine. This variant is present in population databases (rs141482808, ExAC 0.01%). This variant 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.

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