Submissions for variant NM_000492.4(CFTR):c.2260G>A (p.Val754Met)

gnomAD frequency: 0.00171  dbSNP: rs150157202

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000046566	SCV000074579	benign	Cystic fibrosis	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000242825	SCV000304480	likely benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000589543	SCV000330919	uncertain significance	not provided	2018-03-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589543	SCV000601072	likely benign	not provided	2023-09-20	criteria provided, single submitter	clinical testing	In the published literature, this variant has been observed in unaffected individuals who also carry a CF-causing mutation on the other chromosome, indicating that this variant is not associated with classic CF (PMID: 23276700 (2013), 25824995 (2015)). However, individuals with this variant in combination with a CF-causing mutation on the other chromosome may develop mild symptoms in select organ systems and/or be diagnosed as having a CFTR-related disorder (PMIDs: 10376575 (1999), 17413420 (2007), 15987793 (2005), 17003641 (2006), 16786510 (2006), and 25797027 (2015)). In addition, in vitro functional studies indicate that this variant does not prevent chloride conduction by the CFTR protein (PMID: 25797027 (2015) and 23974870 (2013)), but it may reduce the level of mature CFTR protein (PMID: 25797027 (2015)). The frequency of this variant in the general population, 0.004 (94/26044 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589543	SCV000603060	uncertain significance	not provided	2023-03-10	criteria provided, single submitter	clinical testing	The CFTR c.2260G>A; p.Val754Met variant (rs150157202) has been reported in patients diagnosed with cystic fibrosis (Loumi 2008, Orozco 2000), but was found to be in-cis with truncating variants (Lucarelli 2015, Niel 2006). The variant has also been found in individuals without clinical symptoms of cystic fibrosis, in-trans with other pathogenic variants (Krenkova 2013, Niel 2006, Sosnay 2013), and thus is considered non-CF causing (CFTR2 database). Functional characterization of the variant protein also indicates no defects in protein maturation or chloride transport activity (Sosnay 2013). However, the variant has been reported in multiple individuals with chronic pancreatitis (Niel 2006, Keiles 2006) and oligospermy (Gallati 2009), and thus its role in CFTR-related disorders is uncertain. The p.Val754Met variant is listed in ClinVar (Variation ID: 53465) and is observed in the general population at a frequency of 0.18% (509/280,228 alleles, including 2 homozygotes) in the Genome Aggregation Database. The valine at residue 754 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.518). Although the p.Val754Met variant is not associated with classic cystic fibrosis, its clinical significance for CFTR-related disorders is uncertain. References: CFTR2 database: http://cftr2.org/ Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 Nov;19(5):685-94. PMID: 20021716. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. Krenkova P et al. Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations. J Cyst Fibros. 2013 Sep;12(5):532-7. PMID: 23276700. Loumi O et al. CFTR mutations in the Algerian population. J Cyst Fibros. 2008 Jan;7(1):54-9. PMID: 17572159. Lucarelli M et al. A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis. Mol Med. 2015 Apr 21;21:257-75. PMID: 25910067. Niel F et al. A new large CFTR rearrangement illustrates the importance of searching for complex alleles. Hum Mutat. 2006 Jul;27(7):716-7. PMID: 16786510 Orozco L et al. Spectrum of CFTR mutations in Mexican cystic fibrosis patients: identification of five novel mutations (W1098C, 846delT, P750L, 4160insGGGG and 297-1G-->A). Hum Genet. 2000 Mar;106(3):360-5. PMID: 10798368
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589543	SCV000696893	benign	not provided	2016-06-16	criteria provided, single submitter	clinical testing	Variant Summary: The c.2260G>A (p.Val754Met) in CFTR gene is a missense change that involves a non- conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant was found in the large and broad cohorts of ExAC project at an allele frequency of 0.0019 (233/117214 chrs tested, including 1 homozygous occurrence). This frequency does not exceed the maximal expected allele frequency of a disease causing CFTR allele (0.013). Several CF patients, who have been found to be carriers of the variant of interest also carried known pathogenic variants in cis and in trans. In addition variant was seen in apparently healthy individuals with severe mutation on the other chromosomes (Sosnay , 2013). In vivo/vitro functional studies showed that the Cl- conductance of CFTR channels formed by V754M CFTR protein is not impaired suggesting that the variant does not affect Cl- channel function of CFTR (Sosnay, 2013). In conclusion, while a mild detrimental effect p.Val754Met resulting in CF spectrum diseases could not be definitely ruled out, there are strong lines of evidence against a severe deleterious effect and its association with CF. Lastly, CFTR2.org classify variant as NON-disease causing. Taking together, by applying ACMG guidelines the variant was classified as Benign.
Counsyl	RCV000046566	SCV000798336	uncertain significance	Cystic fibrosis	2018-03-09	criteria provided, single submitter	clinical testing
Mendelics	RCV000046566	SCV000886142	benign	Cystic fibrosis	2023-08-22	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000046566	SCV000992336	benign	Cystic fibrosis	2019-08-09	criteria provided, single submitter	clinical testing
CFTR-France	RCV000046566	SCV001169168	benign	Cystic fibrosis	2018-03-26	criteria provided, single submitter	curation	the variant does not result in CFTR-RD neither
Ambry Genetics	RCV000046566	SCV001175747	likely benign	Cystic fibrosis	2018-06-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV001163690	SCV001325754	uncertain significance	CFTR-related disorders	2017-04-27	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.
Sema4, Sema4	RCV002255272	SCV002529691	likely benign	Hereditary pancreatitis	2020-10-12	criteria provided, single submitter	curation
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000589543	SCV001740123	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000589543	SCV001928592	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000589543	SCV001954436	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000589543	SCV001969998	likely benign	not provided		no assertion criteria provided	clinical testing