ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3873G>C (p.Gln1291His) (rs121909015)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000007572 SCV000800485 uncertain significance Cystic fibrosis 2017-01-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780123 SCV000917167 pathogenic not specified 2018-09-07 criteria provided, single submitter clinical testing Variant summary: CFTR c.3873G>C (p.Gln1291His) results in a non-conservative amino acid change in the encoded protein sequence. The variant also alters a conserved nucleotide located to the last nucleotide of exon 20, affecting a canonical splice site and therefore could alter mRNA splicing, leading to a significantly altered protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: 4/5 predict the variant weakens a 5' splicing donor site. At least one publication reported experimental evidence that the variant resulted in both a 'correct' (although altered) splice product, and an incorrectly spliced mRNA from the use of a nearby cryptic splice site (29 bases into the adjacent intron), where the inclusion of the intronic sequence resulted in an in-frame, downstream stop codon (Jones1992). Another functional study demonstrated that the Gln1291His variant protein showed normal processing and trafficking to the plasma membrane, as well as unaltered single channel gating properties in the presence of ATP; however the data suggested the disruption of adenylate kinase-dependent gating that might affect channel activity in airway epithelia (Dong 2015). The variant allele was found at a frequency of 8.1e-06 in 245448 control chromosomes (gnomAD and publications). The variant, c.3873G>C, has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Jones 1992, Dorfman 2010, Baker 2011). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000007572 SCV001574473 likely pathogenic Cystic fibrosis 2020-02-19 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 1291 of the CFTR protein (p.Gln1291His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 23 of the CFTR coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121909015, ExAC 0.002%). This variant has been observed in individual(s) with CFTR-related conditions (PMID: 1284466, 21388895, 22423042, 7551394). ClinVar contains an entry for this variant (Variation ID: 7152). This variant has been reported to have insufficient data to determine the effect on CFTR protein function (PMID: 25887396). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 1284466). This variant disrupts the p.Gln1291 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 7525450), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000007572 SCV000027773 pathogenic Cystic fibrosis 1992-04-01 no assertion criteria provided literature only

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