ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.3415A>G (p.Ile1139Val)

gnomAD frequency: 0.00011  dbSNP: rs397508556
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508519 SCV000603071 uncertain significance not specified 2017-03-30 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000727469 SCV000708800 uncertain significance not provided 2018-07-13 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000727469 SCV001155242 pathogenic not provided 2023-01-01 criteria provided, single submitter clinical testing CFTR: PM1:Strong, PS1, PS3, PP3, BP2
Ambry Genetics RCV001857385 SCV001181692 uncertain significance Cystic fibrosis 2023-09-08 criteria provided, single submitter clinical testing The p.I1139V variant (also known as c.3415A>G), located in coding exon 21 of the CFTR gene, results from an A to G substitution at nucleotide position 3415. The isoleucine at codon 1139 is replaced by valine, an amino acid with highly similar properties. This variant was originally reported in a healthy father of a child who had cystic fibrosis with elevated sweat chloride levels, pancreatic sufficiency, and respiratory disease. The mother was heterozygous for a nonsense variant; however, analysis was not performed in the child (Teng H et al. Hum. Mol. Genet., 1994 Dec;3:2249-50). This alteration was identified in multiple individuals with pancreatitis who carried a pathogenic variant (Keiles S et al. Pancreas, 2006 Oct;33:221-7; Pagin A et al. PLoS One, 2016 Feb;11:e0149426; Ambry internal data). However, this variant has also been detected in trans with a pathogenic mutation in unrelated individuals with normal sweat chloride levels (Ambry internal data). In a functional study, I1139V did not affect protein maturation, but reduced cAMP-activated whole cell chloride currents (Vankeerberghen A et al. FEBS Lett., 1998 Oct;437:1-4). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000508519 SCV001337998 uncertain significance not specified 2023-10-02 criteria provided, single submitter clinical testing Variant summary: CFTR c.3415A>G (p.Ile1139Val) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251530 control chromosomes, predominantly at a frequency of 0.00022 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (0.0001 vs 0.013), allowing no conclusion about variant significance. c.3415A>G has been reported in compound heterozygosity with a second disease-associated variant in at least one individual affected with a non-classic CF-phenotype (Vo_2006). The variant was also presumed to be present in a CF patient (due to its detection in the patient's father) who was not genotyped, although the father also had a second variant in CFTR (3849+10kbC>T) and it was not possible to determine which variant(s) segregated with disease due to no genetic testing being performed on the proband (Teng_1994). The variant was also detected in the U.S. CFTSS (U.S. CF Twin and Sibling Study; Green_2010, exact number of occurrences not specified). Furthermore, c.3415A>G has been reported in multiple individuals with various CFTR-related phenotypes including pancreatitis (where it was found in conjunction with another pathogenic variant in at least 2 individuals) (e.g. Keiles_2006, Pagin_2016, Giefer_2017), CBAVD (e.g. Meschede_2000), oligospermia (e.g. Gallati_2009, Oud_2017) and primary sclerosing cholangitis (PSC; e.g. Sheth_2003), without strong evidence for causality. Experimental evidence evaluating an impact on protein function demonstrated a moderate reduction in chloride channel function but similar permeation properties compared to wild-type protein for this variant as assessed in xenopus oocytes (Vankeerberghen_1998). Although chloride channel function correlates with disease severity in CF/CFTR-RD, this finding has not been further corroborated by additional independent published reports in the literature. The following publications have been ascertained in the context of this evaluation (PMID: 17003641, 12940920, 12783301, 9804160, 10755189, 20021716, 9345100, 10875874, 7881429, 20932301, 16442101, 15784035, 20416310, 28502372, 28801929, 30146269, 26900683, 30091983). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=5) and pathogenic/likely pathogenic (n=3) Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001857385 SCV002168891 uncertain significance Cystic fibrosis 2022-10-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1139 of the CFTR protein (p.Ile1139Val). This variant is present in population databases (rs397508556, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of CFTR-related conditions (PMID: 7881429, 17003641, 20021716, 27171515, 28801929). ClinVar contains an entry for this variant (Variation ID: 53736). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CFTR protein function. Experimental studies have shown that this missense change affects CFTR function (PMID: 9804160). 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.
CFTR-France RCV002281552 SCV002570017 pathogenic CFTR-related disorder 2021-01-18 criteria provided, single submitter curation
Institute of Human Genetics, University of Leipzig Medical Center RCV001857385 SCV002573850 uncertain significance Cystic fibrosis 2022-09-05 criteria provided, single submitter curation This variant was identified in 4 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_SUP, PM2_SUP, PM3, PP3
Revvity Omics, Revvity RCV000727469 SCV003831637 uncertain significance not provided 2022-07-27 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV002281552 SCV004745074 uncertain significance CFTR-related disorder 2024-03-01 criteria provided, single submitter clinical testing The CFTR c.3415A>G variant is predicted to result in the amino acid substitution p.Ile1139Val. This variant was reported presumably in the compound heterozygous state, along with a truncating variant in CFTR, in one patient with cystic fibrosis (inferred from parental studies as deceased proband not available for genetic testing) (Teng et al. 1994. PubMed ID: 7881429). This variant was also reported to be associated with oligospermic/azoospermia (Gallati et al. 2009. PubMed ID: 20021716; Oud et al. 2017. PubMed ID: 28801929) and pancreatitis (Keiles and Kammesheidt. 2006. PubMed ID: 17003641; Pagin et al. 2016. PubMed ID: 26900683; Palermo et al. 2016. PubMed ID: 27171515; Giefer et al. 2017. PubMed ID: 28502372). Functional studies in Xenopus laevis oocytes suggested normal permeability sequence of the mutant CFTR, although reduced chloride currents were observed compared to wild-type protein (Vankeerberghen et al. 1998. PubMed ID: 9804160). This variant is reported in 0.021% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000727469 SCV001740686 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000727469 SCV001964971 pathogenic not provided no assertion criteria provided clinical testing

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