Submissions for variant NM_000492.4(CFTR):c.4031G>C (p.Cys1344Ser)

gnomAD frequency: 0.00002  dbSNP: rs368427311

Total submissions: 9

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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780147	SCV000917192	uncertain significance	not specified	2022-03-04	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 domain and ABC transporter-like 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 2.4e-05 in 251158 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4031G>C has been reported in the literature in a 81 year old individual with Bronchiectasis and normal sweat chloride (<40 mEq/dL) in whom a second variant was not reported (example, Ziedalski_2006). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no direct variant specific experimental evidence demonstrating an impact on protein function has been reported, although Cysteine residues in the nucleotide binding domains have been reported to regulate the conductance state of CFTR channels (Harrington_2002). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000665288	SCV001206980	uncertain significance	Cystic fibrosis	2022-05-24	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1344 of the CFTR protein (p.Cys1344Ser). This variant is present in population databases (rs368427311, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 550522). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR 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.
Genome-Nilou Lab	RCV000665288	SCV002027531	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002493081	SCV002790058	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-10-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000665288	SCV005035822	uncertain significance	Cystic fibrosis	2023-11-27	criteria provided, single submitter	clinical testing	The p.C1344S variant (also known as c.4031G>C), located in coding exon 25 of the CFTR gene, results from a G to C substitution at nucleotide position 4031. The cysteine at codon 1344 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001829831	SCV002075923	uncertain significance	CFTR-related disorder	2018-10-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001829831	SCV005359147	uncertain significance	CFTR-related disorder	2024-03-08	no assertion criteria provided	clinical testing	The CFTR c.4031G>C variant is predicted to result in the amino acid substitution p.Cys1344Ser. This variant was reported in an individual with bronchiectasis and normal sweat chloride level (Ziedalski et al. 2006. PubMed ID: 17035430). Functional studies suggest that the p.Cys1344Ser may reduce the frequency of CFTR channel subconductance opening (Harrington and Kopito. 2002. PubMed ID: 11867445; Figure 4, Frelet and Klein. 2006. PubMed ID: 16442101). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.