ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3415A>G (p.Ile1139Val) (rs397508556)

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Total submissions: 5
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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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727469 SCV000708800 uncertain significance not provided 2018-07-13 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000727469 SCV001155242 uncertain significance not provided 2019-04-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV001020239 SCV001181692 likely pathogenic Inborn genetic diseases 2019-11-15 criteria provided, single submitter clinical testing Deficient protein function by in vitro/ex vivo assay;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes)
Integrated Genetics/Laboratory Corporation of America RCV000508519 SCV001337998 uncertain significance not specified 2020-01-30 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. 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 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 expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (0.00022 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-classical CF-phenotype (Vo_2006). The variant was also presumed to be present in a CF patient who was not genotyped, due to its detection in the patient's father, 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 reported in the literature as being detected in the U.S. CFTSS (U.S. CF Twin and Sibling Study; Green_2010, exact number of occurrences not specified). c.3415A>G has also been detected in multiple patients with various CFTR-related phenotypes, including pancreatitis (e.g. Keiles_2006, Pagin_2016, Giefer_2017), CBAVD (e.g. Meschele_2000), oligospermia (e.g. Gallati_2009, Oud_2017), and primary sclerosing cholangitis (PSC; e.g. Sheth_2003), without strong evidence for causality. At least one publication reports experimental evidence evaluating an impact on protein function. One study reports 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. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Until additional evidence is available, the variant is classified as uncertain significance.

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