Submissions for variant NM_000492.4(CFTR):c.1523T>G (p.Phe508Cys)

gnomAD frequency: 0.00090  dbSNP: rs74571530

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078978	SCV000110845	benign	not specified	2016-04-14	criteria provided, single submitter	clinical testing
Invitae	RCV000007546	SCV000284996	benign	Cystic fibrosis	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000078978	SCV000304473	benign	not specified		criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000078978	SCV000538672	uncertain significance	not specified	2016-04-25	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Benign by Emory. Compund heterozygotes foe this variant and %508del variant were clinically normal, therefore this variant has been classified as benign by Kobayashi et al 1990. Frequency of the variant was higher in individuals with CBAVD (Havasi 2008). Phenotype does not meet reporting criteria.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001281707	SCV000601049	likely benign	not provided	2020-09-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001281707	SCV000608288	pathogenic	not provided	2020-06-09	criteria provided, single submitter	clinical testing	The CFTR c.1523T>G; p.Phe508Cys variant (rs74571530) is reported in the literature in individuals affected with monosymptomatic CFTR-related disorders, such as congenital bilateral absence of the vas deferens or pancreatitis, who also carried an additional pathogenic variant on the opposite chromosome (Dork 1997, Havasi 2008, Meschede 1993, Palermo 2016). This variant has also been reported in asymptomatic individuals (Desgeorges 1994, Kobayashi 1990, Macek 1992), although this may be due to reduced penetrance of CFTR-related disorders. This variant is listed in ClinVar (Variation ID: 7126), and is present in the non-Finnish European population with an overall allele frequency of 0.18% (230/125858 alleles) in the Genome Aggregation Database. The phenylalanine at codon 508 is highly conserved, and computational programs (PolyPhen-2, SIFT) predict that this variant is deleterious. Based on available information, this variant is considered mildly pathogenic and not causative for classic cystic fibrosis. References: Desgeorges M et al. A healthy male with compound and double heterozygosities for delta F508, F508C, and M47OV in exon 10 of the cystic fibrosis gene. Am J Hum Genet. 1994 54(2):384-5. Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997 100(3-4):365-77. Havasi V et al. The role of the F508C mutation in congenital bilateral absence of the vas deferens. Genet Med. 2008 10(12):910-4. Kobayashi K et al. Benign missense variations in the cystic fibrosis gene. Am J Hum Genet. 1990 47(4):611-5. Macek M Jr et al. Missense variations in the cystic fibrosis gene: heteroduplex formation in the F508C mutation. Am J Hum Genet. 1992 Nov;51(5):1173-4. Meschede D et al. Compound heterozygosity for the delta F508 and F508C cystic fibrosis transmembrane conductance regulator (CFTR) mutations in a patient with congenital bilateral aplasia of the vas deferens. Am J Hum Genet. 1993 Jul;53(1):292-3. Palermo JJ et al. Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis. Pancreas. 2016 Oct;45(9):1347-52.
Johns Hopkins Genomics, Johns Hopkins University	RCV000007546	SCV000886893	benign	Cystic fibrosis	2019-10-30	criteria provided, single submitter	clinical testing
CFTR-France	RCV001009496	SCV001169591	pathogenic	CFTR-related disorders	2018-01-29	criteria provided, single submitter	curation
Ambry Genetics	RCV000007546	SCV001172405	uncertain significance	Cystic fibrosis	2023-05-09	criteria provided, single submitter	clinical testing	The p.F508C variant (also known as c.1523T>G), located in coding exon 11 of the CFTR gene, results from a T to G substitution at nucleotide position 1523. The phenylalanine at codon 508 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was first detected in two healthy individuals who also carried the p.F508del mutation on the other chromosome; thus, the authors suggested a benign classification (Kobayashi K et al. Am. J. Hum. Genet., 1990 Oct;47:611-5). Subsequently, p.F508C was detected with another pathogenic mutation in 3 of 182 individuals with congenital bilateral absence of the vas deferens (CBAVD). This same study also described 5 individuals who were compound heterozygous with another pathogenic mutation in a cohort of 5938 individuals suspected to have CF. However, the frequency of the p.F508C variant in this suspected CF population did not significantly differ from that of their control population (Havasi V et al. Genet. Med., 2008 Dec;10:910-4). Functional studies determined that this substitution does not affect CFTR function, protein folding, or the transport of the protein to the cell membrane, but could affect ion channel function, particularly when co-occurring with another alteration (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077; Du K et al. Nat. Struct. Mol. Biol., 2005 Jan;12:17-25; Cui L et al. J. Physiol. (Lond.), 2006 Apr;572:347-58). 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, this variant is unlikely to be causative of classic CF; however, its contribution to the development of a CFTR-related disorder is uncertain. This alteration is thus classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001009496	SCV001323779	uncertain significance	CFTR-related disorders	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV000007546	SCV001822059	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Institute of Reproductive Genetics, University of Münster	RCV001642200	SCV001860331	pathogenic	Obstructive azoospermia	2021-08-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001281707	SCV001962090	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	CFTR: BP2, BS2
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000007546	SCV002507373	benign	Cystic fibrosis	2019-10-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000078978	SCV002518210	benign	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002255993	SCV002529679	likely benign	Hereditary pancreatitis	2020-10-21	criteria provided, single submitter	curation
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002255993	SCV003808092	uncertain significance	Hereditary pancreatitis	2022-04-20	criteria provided, single submitter	clinical testing	ACMG classification criteria: PP3 supporting
OMIM	RCV000007546	SCV000027747	benign	Cystic fibrosis	1990-10-01	no assertion criteria provided	literature only
MAGI's Lab - Research, MAGI Group	RCV001327947	SCV001432725	uncertain significance	Infertility disorder		no assertion criteria provided	provider interpretation
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001009496	SCV002507459	uncertain significance	CFTR-related disorders	2019-10-02	no assertion criteria provided	clinical testing