ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046210 SCV000074223 benign Cystic fibrosis 2019-12-31 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 RCV000781246 SCV000883600 likely benign not specified 2019-01-09 criteria provided, single submitter clinical testing
Mendelics RCV000046210 SCV000886368 uncertain significance Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781246 SCV000919154 likely benign not specified 2019-05-29 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 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. The variant, c.1043T>A, has been reported in the literature in individuals affected with Cystic Fibrosis. However, it has also been found as a homozygous variant in a healthy individual (Molinario_2013) and in a patient who presented with respiratory distress, necrotizing enterocolitis and hyperbilirubinemia but negative sweat test (Hentschel_2012), indicating the variant not to be causative for CF. Additionally, in one family the variant was shown not to co-segregate with the disease (D'Apice_2004). Furthermore, cAMP-dependent activation of rectal tissues from a homozygous patient induced Cl secretory responses in the range of normal tissues which were further augmented by cholinergic co-activation with carbachol. The pattern and magnitude of these responses resembled the characteristics of a non-CF rectal tissue, suggesting a neutral impact for the variant (Hentschel_2012). Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant once as benign, once as likely benign and three times as uncertain significance. 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

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