ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.4031G>C (p.Cys1344Ser) (rs368427311)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665288 SCV000789381 uncertain significance Cystic fibrosis 2017-01-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780147 SCV000917192 uncertain significance not specified 2018-12-07 criteria provided, single submitter clinical testing Variant summary: CFTR c.4031G>C (p.Cys1344Ser) results in a non-conservative amino acid change located in the AAA+ ATPase and ABC transporter-like domains of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 276860 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.4031G>C, has been reported in the literature in one individual affected with Bronchiectasis and normal sweat chloride concentration (Ziedalski_2006). This report does not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000780147 SCV001160036 uncertain significance not specified 2018-10-12 criteria provided, single submitter clinical testing The CFTR c.4031G>C; p.Cys1344Ser variant (rs368427311) is reported in the literature in an individual with bronchiectasis and nontuberculous mycobacterial infection but a normal sweat chloride test (Ziedalski 2006). This variant is found on six chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is reported in ClinVar (Variation ID: 550522). The cysteine at codon 1344 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Cys1344Ser variant is uncertain at this time. References: Ziedalski TM et al. Prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection. Chest. 2006 Oct;130(4):995-1002.
Invitae RCV000665288 SCV001206980 uncertain significance Cystic fibrosis 2019-11-06 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 1344 of the CFTR protein (p.Cys1344Ser). The cysteine residue is weakly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is present in population databases (rs368427311, ExAC 0.009%). This variant has not been reported in the literature in individuals with CFTR-related conditions. This variant has been reported to have conflicting or insufficient data to determine the effect on CFTR protein function (PMID: 16442101). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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