Submissions for variant NM_000492.4(CFTR):c.1021T>C (p.Ser341Pro)

dbSNP: rs397508144

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056338	SCV000071526	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Eurofins Ntd Llc (ga)	RCV000724655	SCV000700810	pathogenic	not provided	2016-10-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004248	SCV001163124	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056338	SCV002260596	pathogenic	Cystic fibrosis	2024-08-28	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 341 of the CFTR protein (p.Ser341Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 23974870; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53167). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 23891399, 30046002). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056338	SCV002500580	pathogenic	Cystic fibrosis	2022-03-22	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1021T>C (p.Ser341Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251226 control chromosomes (gnomAD). c.1021T>C has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Sosnay_2013, McCague_2019, CFTR2 database), including 2 homozygotes (Sickkids database). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function has shown that chloride transport by the variant is less than 1% (e.g.Sosnay_2013, Van Goor_2013). Three ClinVar submitters including an expert panel (CFTR2) have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000724655	SCV002525769	pathogenic	not provided	2021-12-20	criteria provided, single submitter	clinical testing	PP3, PM2, PM3_strong, PS3
Johns Hopkins Genomics, Johns Hopkins University	RCV000056338	SCV002570359	pathogenic	Cystic fibrosis	2022-08-08	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotypic information.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000056338	SCV002573986	likely pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_SUP, PM3, PM2_SUP, PP3, PP4
Ambry Genetics	RCV000056338	SCV002678835	pathogenic	Cystic fibrosis	2018-04-19	criteria provided, single submitter	clinical testing	The p.S341P pathogenic mutation (also known as c.1021T>C), located in coding exon 8 of the CFTR gene, results from a T to C substitution at nucleotide position 1021. The serine at codon 341 is replaced by proline, an amino acid with similar properties. In a cohort of individuals with cystic fibrosis, this mutation was identified in 377 individuals and is associated with elevated sweat chloride levels, and a higher rate of Pseudomonas infection (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In addition, analysis in FRT studies demonstrated reduced CFTR protein levels and undetectable chloride conductance (Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002496707	SCV002808765	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-04-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000724655	SCV003826257	likely pathogenic	not provided	2022-07-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473441	SCV004213397	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-09-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000056338	SCV001456059	pathogenic	Cystic fibrosis	2020-09-16	no assertion criteria provided	clinical testing