Submissions for variant NM_000492.4(CFTR):c.476T>C (p.Leu159Ser)

gnomAD frequency: 0.00001  dbSNP: rs397508727

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000496886	SCV000588144	likely pathogenic	Congenital bilateral aplasia of vas deferens from CFTR mutation	2017-02-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811331	SCV001472175	likely pathogenic	not provided	2023-06-12	criteria provided, single submitter	clinical testing	The CFTR c.476T>C; p.Leu159Ser variant (rs397508727) is reported in the literature in the compound heterozygous state with a second pathogenic variant in individuals affected with pancreatic sufficient cystic fibrosis (Alonso 2007, Goubau 2009). This variant is also reported in ClinVar (Variation ID: 53962). It is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.816). Based on available information, this variant is considered to be likely pathogenic. References: Alonso MJ et al. Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry. Ann Hum Genet. 2007 Mar;71(Pt 2):194-201. PMID: 17331079. Goubau C et al. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax. 2009 Aug;64(8):683-91. PMID: 19318346.
Invitae	RCV001852983	SCV002115998	pathogenic	Cystic fibrosis	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 159 of the CFTR protein (p.Leu159Ser). This variant is present in population databases (rs397508727, gnomAD 0.002%). This missense change has been observed in individual(s) with CFTR-related conditions and/or cystic fibrosis (PMID: 19318346, 28603918, 28830496, 29983195; Invitae). ClinVar contains an entry for this variant (Variation ID: 53962). 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%. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001852983	SCV002573971	uncertain significance	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 2 unrelated patients 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: PM3, PM2_SUP, PP3
Ambry Genetics	RCV001852983	SCV002634711	pathogenic	Cystic fibrosis	2017-05-25	criteria provided, single submitter	clinical testing	The p.L159S pathogenic mutation (also known as c.476T>C), located in coding exon 4 of the CFTR gene, results from a T to C substitution at nucleotide position 476. The leucine at codon 159 is replaced by serine, an amino acid with dissimilar properties. This mutation was first reported as identified on two cystic fibrosis chromosomes; however, the complete genotypes were not provided (Alonso MJ et al. Ann. Hum. Genet., 2007 Mar;71:194-201; Storm K et al. J. Cyst. Fibros., 2007 Nov;6:371-5). This mutation was identified in two individuals in conjunction with p.F508del; one individual had pancreatic sufficient cystic fibrosis and the second individual had an intermediate sweat chloride level (Goubau C et al. Thorax, 2009 Aug;64:683-91). Based on our internal structural analysis, this alteration is more destabilizing than known pathogenic alterations within the same domain (Flachowsky S et al. Zentralbl Gynakol, 1986;108:383-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001852983	SCV002819846	likely pathogenic	Cystic fibrosis	2024-04-23	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.476T>C (p.Leu159Ser) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248770 control chromosomes (gnomAD). c.476T>C has been reported in the literature in individuals affected with Cystic Fibrosis or related disorders (e.g. Goubau_2009, Trujillano_2013, Claustres_2017, Minso_2020). These data indicate that the variant is likely to be associated with disease. 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: 17331079, 23687349, 19318346, 17481968, 28603918, 33020115). ClinVar contains an entry for this variant (Variation ID: 53962). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003466916	SCV004215203	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-01-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001831792	SCV002080148	likely pathogenic	CFTR-related disorder	2019-07-12	no assertion criteria provided	clinical testing