Submissions for variant NM_000492.4(CFTR):c.4276T>C (p.Ser1426Pro)

gnomAD frequency: 0.00001  dbSNP: rs397508708

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317064	SCV000697022	uncertain significance	not specified	2023-06-15	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.4276T>C (p.Ser1426Pro) results in a non-conservative amino acid change to a well-conserved residue (HGMD) located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251444 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4276T>C has been found in one CBAVD patient published in the literature in a compound heterozygous state with deltaF508 (Steiner_Hum Mut_2011). The UMD database lists one reportedly unpublished CBAVD patient that also carried deltaF508 (phase unknown). It was also found in a heterozygous state without a second variant identified in an infant with respiratory distress (Tanriverdi_2021) and in one with acute pancreatitis (Abu-El-Haija_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21520337, 25735457, 34996830, 36249513, 31088717, 31682332). Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000665842	SCV000790028	uncertain significance	Cystic fibrosis	2017-03-14	criteria provided, single submitter	clinical testing
CFTR-France	RCV001009481	SCV001169576	pathogenic	CFTR-related disorders	2018-01-29	criteria provided, single submitter	curation
Invitae	RCV000665842	SCV002132672	uncertain significance	Cystic fibrosis	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1426 of the CFTR protein (p.Ser1426Pro). This variant is present in population databases (rs397508708, gnomAD 0.006%). This missense change has been observed in individual(s) with congenital bilateral absence of the vas deferens (CBAVD) and/or pancreatitis (PMID: 21520337, 31088717). ClinVar contains an entry for this variant (Variation ID: 53937). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. 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.
Ambry Genetics	RCV000665842	SCV002631586	uncertain significance	Cystic fibrosis	2015-07-28	criteria provided, single submitter	clinical testing	The p.S1426P variant (also known as c.4276T>C), located in coding exon 27 of the CFTR gene, results from a T to C substitution at nucleotide position 4276. The serine at codon 1426 is replaced by proline, an amino acid with similar properties. This variant was reported in one patient with congenital absence of the vas deferens (CAVD) who was also heterozygous for deltaF508, however the phase was unknown (Steiner et al. Hum Mutat. 2011;32: 912). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging by PolyPhen but tolerated by SIFT in silico analyses. Since clinical data on this variant is limited at this time, its clinical significance is unclear.
Natera, Inc.	RCV001009481	SCV002075967	uncertain significance	CFTR-related disorders	2018-07-21	no assertion criteria provided	clinical testing