ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2506G>T (p.Asp836Tyr) (rs201386642)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000224075 SCV000885180 likely pathogenic not provided 2018-04-24 criteria provided, single submitter clinical testing The CFTR c.2506G>T; p.Asp836Tyr variant (rs201386642) has been reported in patients clinically diagnosed with cystic fibrosis(CF) (des Georges 2004, de Gracia 2005, Narzi 2007, CFTR database). Of 9 individuals in the CFTR2 database with one copy of p.Asp836Tyr and one copy of another pathogenic CFTR variant, about one third were pancreatic insufficient (CFTR2 database). This variant, p.Asp836Tyr has also been reported along with two other known severe pathogenic variants (F508del and 2215insG) in two individuals with pancreatic insufficient CF (Salinas 2016). The variant is listed in ClinVar (Variation ID: 53505), and observed in the general population at an overall frequency of 0.04% (121/276962 alleles) in the Genome Aggregation Database, with an increased frequency in Latino population of 0.2% (60/34400 alleles). The aspartate at codon 836 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict that the variant has an impact on the protein. However, in vitro mutagenesis of aspartate 836 did not indicate functional defects consistent with the mechanism of disease (Wang 2012, CFTR2 database). Based on the above information, the p.Asp836Tyr variant is classified as likely pathogenic, with variable clinical phenotypes. REFERENCES CFTR2 database: https://www.cftr2.org/ Sickkids CFTR database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=371 de Garcia J et al. Genotype-phenotype correlation for pulmonary function in cystic fibrosis. Thorax. 2005 Jul;60(7):558-63. des Georges M et al. High heterogeneity of CFTR mutations and unexpected low incidence of cystic fibrosis in the Mediterranean France. J Cyst Fibros. 2004 Dec;3(4):265-72. Narzi L et al. Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up. Clin Genet. 2007 Jul;72(1):39-46. Salinas D et al. Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California. PLoS One. 2016 May 23;11(5):e0155624. Wang G et al. Regulation of activation and processing of the cystic fibrosis transmembrane conductance regulator (CFTR) by a complex electrostatic interaction between the regulatory domain and cytoplasmic loop 3. J Biol Chem. 2012 Nov 23;287(48):40484-92.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224075 SCV000281608 likely pathogenic not provided 2014-11-13 criteria provided, single submitter clinical testing
Counsyl RCV000046610 SCV000800606 uncertain significance Cystic fibrosis 2017-10-18 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000224075 SCV000343987 uncertain significance not provided 2017-10-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000224075 SCV000696904 uncertain significance not provided 2017-08-22 criteria provided, single submitter clinical testing Variant summary:The CFTR c.2506G>T (p.Asp836Tyr) variant involves the alteration of a conserved nucleotide and results in a replacement of an medium size and acidic Aspartic acid (D) with a large size and aromatic Tyrosine (Y) located in the R domain of CFTR, which some evidence suggests may be a functionally important domain (Ma_2000) . 5/5 in silico tools predict damaging outcome for this substitution. The variant was found in 51/121546 control chromosomes from ExAC and literature at a frequency of 0.0004196, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The c.2506G>T variant has been reported in at least 5 CF patients, two of which had negative sweat chloride tests (des Georges_2004, de Garcia_2005, SickKids db pers. corr.). Additionally, two CF patients harbored two pathogenic CFTR variants in addition to the variant of interest indicating the c.2506G>T variant not to be the cause of the disease in these patients. The variant was also detected in a newborn with deltaF508 who showed no signs or symptoms of CF as well as in twins with granulomatous ileocolonic Crohn's disease who both had negative sweat chloride tests and had c.2249C>T (p.Pro750Leu) in other allele which is classified as a possibly disease variant by our lab. No functional studies reporting an effect of this specific variant on CFTR channel activity, or conductance have been reported. Multiple clinical diagnostic laboratories/reputable databases classified this variant in the VUS - likely pathogenic spectrum. Therefore, the variant is likely not associated with classic CF, however its role in non-classic phenotypes remains uncertain. Therefore, until additional evidence becomes available, the variant has been classified as a Variant of Unknown Significance for the non-classic CF phenotype.
Invitae RCV000046610 SCV000074623 benign Cystic fibrosis 2017-09-26 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825894 SCV000967379 uncertain significance not specified 2018-03-06 criteria provided, single submitter clinical testing The p.Asp836Tyr variant in CFTR has been reported in 2 individuals with cystic f ibrosis; however it was unclear if a second CFTR variant was found in these indi viduals (des Georges 2004, Schrijver 2005). It was also identified in the compou nd heterozygous state in 4 individuals who had at least one additional pathogeni c variant in CFTR (de Gracia 2005, Narzi 2007, Salinas 2016). In two of these in dividuals, two other pathogenic variants in CFTR were also identified, suggestin g that the p.Asp836Tyr variant may not be the primary cause of disease (Salinas 2016). This variant has also been reported by other clinical laboratories in Cli nVar (Variation ID# 53505) and has been identified in 0.17% (60/34400) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org; dbSNP rs201386642). Although this variant has been seen in the genera l population, its frequency is not high enough to rule out a pathogenic role. Co mputational prediction tools and conservation analysis do not provide strong sup port for or against an impact to the protein. In summary, due to conflicting evi dence, the clinical significance of the p.Asp836Tyr variant is uncertain. ACMG/A MP Criteria applied: PM3_Strong, BP2.

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