ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2260G>A (p.Val754Met) (rs150157202)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000589543 SCV000603060 uncertain significance not provided 2017-05-01 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 2007), 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 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 observed in the general population at an overall frequency of 0.18% (493/274710 alleles, 1 homozygote) in the Genome Aggregation Database. The valine at residue 754 is weakly conserved and computational algorithms (PolyPhen-2, SIFT) predict that the variant has no impact on the protein. Although the p.Val754Met variant is not associated with classic cystic fibrosis, its clinical significance in pancreatitis patients cannot be determined with certainty. 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; 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; 12(5):532-7. Loumi O et al. CFTR mutations in the Algerian population. J Cyst Fibros. 2008; 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; 21:257-75. Niel F et al. A new large CFTR rearrangement illustrates the importance of searching for complex alleles. Hum Mutat. 2006; 27(7):716-7. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7.
Counsyl RCV000046566 SCV000798336 uncertain significance Cystic fibrosis 2018-03-09 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
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, CFTR2.org classify variant as NON-disease causing. Taking together, by applying ACMG guidelines the variant was classified as Benign.
Invitae RCV000046566 SCV000074579 benign Cystic fibrosis 2017-12-10 criteria provided, single submitter clinical testing
Mendelics RCV000046566 SCV000886142 uncertain significance Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
PreventionGenetics RCV000242825 SCV000304480 likely benign not specified 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

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