ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046610 SCV000074623 benign Cystic fibrosis 2020-12-08 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000825894 SCV000696904 benign not specified 2020-11-23 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. 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 (example, Narzi_2007, deGracia_2005) as well as in patients with pancreatically insufficient classic CF phenotype who had two other pathogenic CFTR variants that could explain the diagnosis (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). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, at-least one of whom has set a final classification as benign while another laboratory has re-classified the variant from likely pathogenic to uncertain significance citing overlapping evidence utilized in the context of this evaluation (Benign, n=1; VUS, n=5). Furthermore, the CFTR2 database reports this variant as not causative of CF. Based on the absence of concrete evidence supporting a disease causing outcome in literature spanning over 15 years as evidence outlined above, the variant is re-classified as benign.
Counsyl RCV000046610 SCV000800606 uncertain significance Cystic fibrosis 2017-10-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282966 SCV000885180 uncertain significance none provided 2020-01-16 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). 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 0.18% (62/35414 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). Due to conflicting information, the clinical significance of the p.Asp836Tyr variant is uncertain at this time. References: CFTR2 database: 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; 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 2020-03-19 criteria provided, single submitter clinical testing The p.D836Y variant (also known as c.2506G>T), located in coding exon 15 of the CFTR gene, results from a G to T substitution at nucleotide position 2506. The aspartic acid at codon 836 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was reported in trans with the p.F508del mutation in a newborn with a negative newborn screen and sweat test (Narzi L et al. Clin. Genet., 2007 Jul;72:39-46). In addition, this alteration was identified in an individual who had p.F508del and normal sweat test (de Gracia J et al. Thorax, 2005 Jul;60:558-63), as well as two affected newborns that had two known pathogenic mutations in CFTR (Salinas DB et al. PLoS ONE, 2016 May;11:e0155624); however, the phase is not known. This alteration was also described in study cohorts of cystic fibrosis; however, clinical details were limited (des Georges M et al. J. Cyst. Fibros., 2004 Dec;3:265-72; Schrijver I et al. J Mol Diagn, 2005 May;7:289-99). In CFBE cells, this variant demonstrated 122% of wild type CFTR function (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Nilou-Genome Lab RCV000046610 SCV001822110 uncertain significance Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing

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