ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1920T>C (p.Phe640=) (rs145877746)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000242518 SCV000304477 likely benign not specified criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725286 SCV000335702 uncertain significance not provided 2018-02-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000725286 SCV000602986 benign not provided 2018-05-16 criteria provided, single submitter clinical testing
Invitae RCV001087241 SCV000751426 likely benign Cystic fibrosis 2020-11-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000242518 SCV000919151 benign not specified 2018-02-21 criteria provided, single submitter clinical testing Variant summary: CFTR c.1920T>C alters a non-conserved nucleotide resulting in a synonymous change (p.Phe640=). 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.7e-05 in 276596 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (4.7e-05 vs 0.013), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1920T>C in individuals affected with Cystic Fibrosis and no experimental evidence demonstrating its impact on protein function have been reported via publications. The variant was reported in the databases to be present on the same allele as a complex pathogenic allele (c.220C>T_c.601G>A_c.3808G>A). In addition, our laboratory has identified the variant in numerous (>20) individuals with the same pathogenic complex allele, and in several of these cases a second pathogenic CFTR variant was also identified (e.g. p.Phe508del (in 2 cases), p.Ile507del (in one case), p.Arg1162X (in one case), c.5T_TG12 (in one case)). These co-occurrences with other pathogenic variants provide supporting evidence for a benign role. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, where one laboratory classified the variant as benign, and the other laboratory as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics RCV001013703 SCV001174323 likely benign Inborn genetic diseases 2014-11-07 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Johns Hopkins Genomics, Johns Hopkins University RCV001087241 SCV001430644 likely benign Cystic fibrosis 2020-06-11 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV001087241 SCV001822092 likely benign Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV001589232 SCV001822093 uncertain significance Congenital bilateral aplasia of vas deferens from CFTR mutation 2021-07-22 criteria provided, single submitter clinical testing

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