ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2260G>A (p.Val754Met) (rs150157202)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046566 SCV000074579 benign Cystic fibrosis 2019-12-31 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000242825 SCV000304480 likely benign not specified criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000589543 SCV000330919 uncertain significance not provided 2018-03-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000242825 SCV000601072 likely benign not specified 2016-10-07 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000242825 SCV000603060 uncertain significance not specified 2018-09-06 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) 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 algorithms (PolyPhen-2, SIFT) predict that the variant is tolerated. Although the p.Val754Met variant is not associated with classic cystic fibrosis, its clinical significance in pancreatitis patients is uncertain. REFERENCES CFTR2 database: 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. 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. Loumi O et al. CFTR mutations in the Algerian population. J Cyst Fibros. 2008 Jan;7(1):54-9. 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. 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. 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. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7.
Integrated Genetics/Laboratory Corporation of America 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, 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 uncertain significance Cystic fibrosis 2018-11-05 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 RCV001014969 SCV001175747 likely benign Inborn genetic diseases 2018-06-04 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Intact protein function observed by in vitro/ex vivo assays;Other data supporting benign classification;Seen in conjunction with two deleterious mutations confirmed in trans in symptomatic individuals
Illumina Clinical Services Laboratory,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.

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