ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1043T>A (p.Met348Lys) (rs142920240)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046210 SCV000074223 benign Cystic fibrosis 2020-11-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000339107 SCV000345968 uncertain significance not provided 2016-09-16 criteria provided, single submitter clinical testing
Counsyl RCV000046210 SCV000796944 uncertain significance Cystic fibrosis 2018-01-08 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283413 SCV000883600 likely benign none provided 2020-03-15 criteria provided, single submitter clinical testing
Mendelics RCV000046210 SCV000886368 uncertain significance Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781246 SCV000919154 likely benign not specified 2021-05-18 criteria provided, single submitter clinical testing Variant summary: CFTR c.1043T>A (p.Met348Lys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251178 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00014 vs 0.013), allowing no conclusion about variant significance. c.1043T>A has been reported in the literature in individuals affected with Cystic Fibrosis (CF) (example: DApice_2004, Liechti-Gallati_1999). However, it has also been found in a healthy homozygous individual (Molinario_2013) and in a patient who presented with respiratory distress, necrotizing enterocolitis and hyperbilirubinemia but a negative sweat test (Hentschel_2012), indicating the variant was not causative for CF. In another family the variant was shown not to co-segregate with the disease (D'Apice_2004). Additionally, the variant has also been found in cis with another pathogenic variant in a CBAVD (Congenital Bilateral Absence of Vas Deferens) and a CF patient with pancreatic insufficiency (Lucarelli_2015). Electrophysiological assessment of CFTR in native rectal epithelium of the patient homozygous for this variant demonstrated normal Cl- secretion (Hentschel_2012). Eight ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=5) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics RCV001009786 SCV001169897 likely benign Inborn genetic diseases 2019-04-01 criteria provided, single submitter clinical testing Intact protein function observed by in vitro/ex vivo assays;Seen in conjunction with two deleterious mutations confirmed in trans in symptomatic individuals
Johns Hopkins Genomics, Johns Hopkins University RCV000046210 SCV001425327 likely benign Cystic fibrosis 2020-05-07 criteria provided, single submitter clinical testing
Pars Genome Lab RCV000046210 SCV001652835 uncertain significance Cystic fibrosis 2021-05-18 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000046210 SCV001822032 uncertain significance Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
Natera, Inc. RCV000046210 SCV001453956 likely benign Cystic fibrosis 2019-08-06 no assertion criteria provided clinical testing

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