Submissions for variant NM_000492.4(CFTR):c.418C>T (p.Pro140Ser)

gnomAD frequency: 0.00019  dbSNP: rs145900055

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506712	SCV000601118	uncertain significance	not specified	2017-01-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000506712	SCV000697011	uncertain significance	not specified	2024-06-24	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.418C>T (p.Pro140Ser) results in a non-conservative amino acid change located in the first transmembrane domain (IPR011527) 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 0.00014 in 263036 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in CFTR causing Classic Cystic Fibrosis (0.013), allowing no conclusion about variant significance. c.418C>T has been reported in the literature in individuals affected with Cystic Fibrosis (e.g. Schrijver_2016, Salinas_2023) without strong evidence for or against pathogenicity. It has also been reported in the literature as a variant of uncertain significance (e.g. Monaghan_2004; Audrezet_2008). These reports do not provide unequivocal conclusions about association of the variant with Classic Cystic Fibrosis. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately (Gt channel conductance) 12% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 18687795, 32777524, 15354332, 26708955, 17380060, 36409994, 38388235). ClinVar contains an entry for this variant (Variation ID: 53912). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Eurofins Ntd Llc (ga)	RCV000590469	SCV000704520	uncertain significance	not provided	2017-10-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765922	SCV000897342	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2022-04-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590469	SCV001158528	uncertain significance	not provided	2022-12-28	criteria provided, single submitter	clinical testing	The CFTR c.418C>T; p.Pro140Ser variant (rs145900055) is reported in the literature in individuals affected with cystic fibrosis or CFTR-related disorders, though it was not demonstrated to be disease-causing (Luo 2021, Schrijver 2016, SickKids CFTR database). This variant is also reported in ClinVar (Variation ID: 53912). It is found in the general population with an overall allele frequency of 0.02% (43/282098 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.817). However, due to limited information, the clinical significance of this variant is uncertain at this time. References: Luo S et al. Mutation analysis of the cystic fibrosis transmembrane conductance regulator gene in Chinese congenital absence of vas deferens patients. Gene. 2021 Jan 10;765:145045. PMID: 32777524. SickKids CFTR database: http://www.genet.sickkids.on.ca/ Schrijver I et al. The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing. J Mol Diagn. 2016 Jan;18(1):39-50. PMID: 26708955.
Ambry Genetics	RCV001272206	SCV001183697	uncertain significance	Cystic fibrosis	2023-03-02	criteria provided, single submitter	clinical testing	The p.P140S variant (also known as c.418C>T), located in coding exon 4 of the CFTR gene, results from a C to T substitution at nucleotide position 418. The proline at codon 140 is replaced by serine, an amino acid with similar properties. This variant was identified in an African American individual undergoing carrier screening (Monaghan KG et al. Genet. Med, 2004;6:141-4). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001163274	SCV001325297	uncertain significance	CFTR-related disorder	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001272206	SCV001511353	uncertain significance	Cystic fibrosis	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 140 of the CFTR protein (p.Pro140Ser). This variant is present in population databases (rs145900055, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of CFTR-related conditions (PMID: 15354332, 26708955). ClinVar contains an entry for this variant (Variation ID: 53912). 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 not expected to disrupt CFTR protein function. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000590469	SCV001715937	uncertain significance	not provided	2022-05-12	criteria provided, single submitter	clinical testing	PP3
Genome-Nilou Lab	RCV001272206	SCV002027349	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257390	SCV002529725	uncertain significance	Hereditary pancreatitis	2021-04-14	criteria provided, single submitter	curation
Johns Hopkins Genomics, Johns Hopkins University	RCV001272206	SCV002570381	uncertain significance	Cystic fibrosis	2022-07-23	criteria provided, single submitter	clinical testing	CFTR c.418C>T has been identified in multiple individuals with features of cystic fibrosis and has an entry in ClinVar. This variant (rs145900055) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the East Asian subpopulation (gnomAD: 6/5186 alleles; 0.1157%, no homozygotes). BayPR, an algorithm that uses population data to assign disease liability to variants, predicts that this variant is unlikely to be CF causing. Of three bioinformatics tools queried, one/two predict that the substitution would be damaging while one predicts that it would be tolerated. The proline residue at this position is evolutionarily conserved across most species assessed. Due to insufficient evidence that this variant is deleterious, we consider the clinical significance of c.418C>T to be uncertain at this time.
Baylor Genetics	RCV004566882	SCV005057456	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1	2023-12-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001272206	SCV001453948	uncertain significance	Cystic fibrosis	2017-05-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001163274	SCV004111229	uncertain significance	CFTR-related disorder	2024-05-10	no assertion criteria provided	clinical testing	The CFTR c.418C>T variant is predicted to result in the amino acid substitution p.Pro140Ser. This variant has been previously reported a patient with disseminated bronchiectasis (Schrijver I et al 2016. PubMed ID: 26708955; http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=99). A different missense change at the same position (p.Pro140Leu) has also been reported in a patient with mild bronchitis (http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=802). This variant is reported in 0.035% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.