ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.350G>T (p.Arg117Leu) (rs78655421)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000577295 SCV000800064 uncertain significance Cystic fibrosis 2018-05-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985692 SCV001134140 uncertain significance not provided 2019-06-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000577295 SCV001363742 likely pathogenic Cystic fibrosis 2020-10-05 criteria provided, single submitter clinical testing Variant summary: CFTR c.350G>T (p.Arg117Leu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 250954 control chromosomes. c.350G>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Ferec_1995, Wallace_2003, D'Apice_2004). Several investigators have also reported that this variant is part of a complex allele with CFTR c.2991G>C (p.Leu997Phe) in patients with cystic fibrosis (Lucarelli_2010, Lucarelli_2015, Terlizzi_2016). Clinical evaluation of patients showed that p.Leu997Phe could be associated to CFTR-RD while the p.[Arg117Leu;Leu997Phe] is associated with a mild CF phenotype (Lucarelli_2010). The c.2991G>C variant, however, is found at a much higher frequency in controls (approximately 0.0022 in the gnomAD database). At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in impaired chloride channel stability (Hammerle_2001) and impaired CFTR function (Han_2018). These data indicate that the variant in isolation may be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=1, VUS, n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV000577295 SCV001433650 pathogenic Cystic fibrosis 2019-12-08 criteria provided, single submitter clinical testing CFTR variant associated with variable clinical consequences. See www.CFTR2.org for phenotype information.
Invitae RCV000577295 SCV001583153 pathogenic Cystic fibrosis 2020-09-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 117 of the CFTR protein (p.Arg117Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs78655421, ExAC 0.006%). This variant has been observed in combination with another CFTR variant in several individuals and families affected with CFTR-related disorders (PMID: 20706124, 27738188). This variant is also known as c.482G>T (p.Arg117Leu). ClinVar contains an entry for this variant (Variation ID: 53765). This variant has been reported to affect CFTR protein function (PMID: 11278813, 30046002). This variant disrupts the p.Arg117 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 21783433, 23974870, 7525450, 22658665, 15482777, 24586523), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Nilou-Genome Lab RCV000577295 SCV001821994 likely pathogenic Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577295 SCV000679441 not provided Cystic fibrosis no assertion provided literature only

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