Submissions for variant NM_000492.3(CFTR):c.2502T>G (p.Phe834Leu) (rs200735475)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000542704	SCV000625737	uncertain significance	Cystic fibrosis	2019-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine with leucine at codon 834 of the CFTR protein (p.Phe834Leu). The phenylalanine residue is weakly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs200735475, ExAC 0.1%). This variant has been reported in combination with another CFTR variant in individuals affected with chronic pancreatitis or cystic fibrosis (PMID: 17003641, 21521896). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America	RCV001001015	SCV000696903	uncertain significance	not specified	2019-09-19	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2502T>G (p.Phe834Leu) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 252066 control chromosomes (gnomAD, exomes only). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00029 vs 0.013), allowing no conclusion about variant significance. c.2502T>G has been reported in the literature in individuals affected with Cystic Fibrosis and Pancreatitis (e.g. Soltysova_2017, Keiles_2006, Godoy_2011) without strong evidence of causality. These reports therefore, do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000542704	SCV000796974	uncertain significance	Cystic fibrosis	2018-01-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001001015	SCV001158123	uncertain significance	not specified	2019-01-16	criteria provided, single submitter	clinical testing	The CFTR c.2502T>G; p.Phe834Leu variant (rs200735475) is reported in the literature in the compound heterozygous state in two individuals affected with chronic pancreatitis, and in one individual with cystic fibrosis but no second variant or specific clinical phenotype described (Keiles 2006, Soltysova 2018). This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 455769), and is found in the Finnish European population with an allele frequency of 0.13% (32/25,102 alleles) in the Genome Aggregation Database. The phenylalanine at codon 834 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Phe834Leu variant is uncertain at this time. References: Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 33(3):221-7. Soltysova A et al. Comprehensive genetic study of cystic fibrosis in Slovak patients in 25 years of genetic diagnostics. Clin Respir J. 2018 Mar;12(3):1197-1206.