Submissions for variant NM_000492.4(CFTR):c.1558G>T (p.Val520Phe)

dbSNP: rs77646904

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007570	SCV000071532	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781233	SCV000919138	pathogenic	not specified	2017-09-13	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.1558G>T (p.Val520Phe) variant located in the P-loop containing nucleoside triphosphate hydrolase (via InterPro) involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/276844 control chromosomes at a frequency of 0.0000072, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant of interest has been reported in multiple affected CF pts (Sosnay_2013). A function study, Van Goor_2013, found the variant to significantly affect CFTR processing and Cl- transport. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics	RCV001004460	SCV001163505	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000007570	SCV001169467	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000007570	SCV001194058	pathogenic	Cystic fibrosis	2019-12-04	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.1558G>T(V520F) is classified as pathogenic in the context of cystic fibrosis and is associated with classic disease. Sources cited for classification include the following: PMID 1284466, 23974870 and 18456578. Classification of NM_000492.3(CFTR):c.1558G>T(V520F) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007570	SCV001582240	pathogenic	Cystic fibrosis	2024-04-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 520 of the CFTR protein (p.Val520Phe). This variant is present in population databases (rs77646904, gnomAD 0.002%). This missense change has been observed in individuals with cystic fibrosis (PMID: 1284466, 1376016, 22658665, 23974870). ClinVar contains an entry for this variant (Variation ID: 7150). 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%. Experimental studies have shown that this missense change affects CFTR function (PMID: 23891399, 23974870). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000007570	SCV002704397	pathogenic	Cystic fibrosis	2023-12-20	criteria provided, single submitter	clinical testing	The c.1558G>T (p.V520F) alteration is located in exon 11 (coding exon 11) of the CFTR gene. This alteration results from a G to T substitution at nucleotide position 1558, causing the valine (V) at amino acid position 520 to be replaced by a phenylalanine (F). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/282480) total alleles studied. The highest observed frequency was 0.002% (2/128982) of European (non-Finnish) alleles. This variant was first identified in 3 out of 42 cystic fibrosis chromosomes (Jones, 1992). Additionally, this variant is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay, 2013). This amino acid position is well conserved in available vertebrate species. Functional studies found that this mutation results in very low levels of mature CFTR protein and little to no chloride conductance (Sosnay, 2013; Van Goor, 2014; Hirtz, 2004). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV001826436	SCV004117586	pathogenic	CFTR-related disorder	2023-05-22	criteria provided, single submitter	clinical testing	The CFTR c.1558G>T variant is predicted to result in the amino acid substitution p.Val520Phe. This variant has been reported in multiple individuals with cystic fibrosis (see for example, Jones et al 1992. PubMed ID: 1284466; Van Goor et al 2013. PubMed ID: 23891399). An in vitro experimental study suggests this variant diminishes expression of the CFTR protein (Avramescu et al 2017. PubMed ID: 29040544). This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117199683-G-T) and has been interpreted by multiple laboratories in ClinVar as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/7150/). This variant is interpreted as pathogenic.
Baylor Genetics	RCV003473023	SCV004213333	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-10-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000007570	SCV005877616	pathogenic	Cystic fibrosis	2024-08-13	criteria provided, single submitter	clinical testing	The CFTR c.1558G>T; p.Val520Phe variant (rs77646904, ClinVar Variation ID: 7150) is reported in over 100 cystic fibrosis individuals with an average sweat chloride of 101mEq/L and 92% of these individuals reported to be pancreatic insufficient (see CFTR2 database). This variant is only found on two alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.871). In support of these predictions, functional analyses demonstrate an effect of this variant on CFTR quantity and function (see CFTR2 database, Avramescu 2017, Van Goor 2014). Based on available information, this variant is considered to be pathogenic. References: Link to CFTR2 database: https://cftr2.org/ Avramescu RG et al. Mutation-specific downregulation of CFTR2 variants by gating potentiators. Hum Mol Genet. 2017 Dec 15;26(24):4873-4885. PMID: 29040544. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 Jan;13(1):29-36. PMID: 23891399.
OMIM	RCV000007570	SCV000027771	pathogenic	Cystic fibrosis	1992-04-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528232	SCV001739616	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001528232	SCV001955256	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826436	SCV002080614	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing