ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046610 SCV000074623 benign Cystic fibrosis 2019-12-31 criteria provided, single submitter clinical testing
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
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 RCV000825894 SCV000696904 likely benign not specified 2019-04-12 criteria provided, single submitter clinical testing Variant summary: CFTR c.2506G>T (p.Asp836Tyr) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) of the encoded protein sequence (some evidence suggests this may be a functionally important domain (Ma_2000)). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 277324 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (0.00044 vs 0.013), allowing no conclusion about variant significance. The variant, c.2506G>T, has been reported in the literature in compound heterozygosity with deltaF508 in patients with an equivocal diagnosis of CF as evidenced by negative sweat chloride levels and pancreatic sufficiency as well as in patients with classic pancreatically insufficient CF who had two other pathogenic CFTR variants that could explain the diagnosis (Narzi_2007, deGracia_2005, Salinas_2016). These data provide supportive evidence for a benign role. Furthermore, in a recent study evaluating CFTR function by short circuit current measurement in a cell system, the variant of interest was found to have 121% of WT-CFTR function (Raraigh _2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Benign X1; Likely pathogenic X2; uncertain significance X2). Based on the evidence outlined above, the variant is classified as likely benign in the context of classic CF although the possibility of an association with other atypical CFTR phenotypes cannot be excluded.
Counsyl RCV000046610 SCV000800606 uncertain significance Cystic fibrosis 2017-10-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000825894 SCV000885180 uncertain significance not specified 2019-04-09 criteria provided, single submitter clinical testing The CFTR c.2506G>T; p.Asp836Tyr variant (rs201386642) has been reported in patients with diagnoses or symptoms of CF (des Georges 2004, de Gracia 2005, Schrijver 2005, CFTR2 database). Of 7 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). However, p.Asp836Tyr has also been reported in two individuals with pancreatic-insufficient CF (Salinas 2016) who were compound heterozygotes for two known severe pathogenic variants (F508del and 2215insG). The p.Asp836Tyr variant is listed in ClinVar (Variation ID: 53505) and is found in the Latino population with an overall frequency of 0.2% (60/34400 alleles) in the Genome Aggregation Database. 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, the p.Asp836Tyr variant exhibits wildtype chloride channel activity in conductance assays (Raraigh 2018, CFTR2 database). Due to conflicting information, the clinical significance of the p.Asp836Tyr variant is uncertain at this time. REFERENCES CFTR2 database: https://www.cftr2.org/ Sickkids CFTR database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=371 de Gracia 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. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. 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. Schrijver I et al. Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum. J Mol Diagn. 2005 May;7(2):289-99.
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.
Ambry Genetics RCV001015785 SCV001176659 uncertain significance Inborn genetic diseases 2019-03-08 criteria provided, single submitter clinical testing Insufficient evidence

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