ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.4123C>A (p.His1375Asn) (rs146947665)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047079 SCV000075092 uncertain significance Cystic fibrosis 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces histidine with asparagine at codon 1375 of the CFTR protein (p.His1375Asn). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and asparagine. This variant is present in population databases (rs146947665, ExAC 0.007%). This variant has been observed in an individual affected with chronic pancreatits and/or CFTR-related metabolic syndrome (PMID: 19202204, 23810505). . ClinVar contains an entry for this variant (Variation ID: 53894). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Counsyl RCV000047079 SCV000795528 uncertain significance Cystic fibrosis 2017-11-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000731229 SCV000859017 uncertain significance not provided 2017-12-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002180 SCV001160050 uncertain significance not specified 2018-10-18 criteria provided, single submitter clinical testing The CFTR c.4123C>A; p.His1375Asn variant (rs146947665), is reported in the literature in individuals affected with chronic pancreatitis (Kolesar 2008) or CFTR-related metabolic syndrome (Prach 2013), who also carry the common F508del pathogenic variant on the opposite chromosome. This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 53894) and is found in the non-Finnish European population with an allele frequency of 0.014% (18/126,452 alleles) in the Genome Aggregation Database. The histidine at codon 1375 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.His1375Asn variant is uncertain at this time. References: Kolesar P et al. Mutation analysis of the CFTR gene in Slovak cystic fibrosis patients by DHPLC and subsequent sequencing: identification of four novel mutations. Gen Physiol Biophys. 2008 Dec;27(4):299-305. Prach L et al. Novel CFTR variants identified during the first 3 years of cystic fibrosis newborn screening in California. J Mol Diagn. 2013 Sep;15(5):710-22.

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