ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.*2G>A (rs150914702)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000176720 SCV000228426 uncertain significance not provided 2017-04-12 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002168 SCV001160027 uncertain significance not specified 2018-10-09 criteria provided, single submitter clinical testing The CFTR c.*2G>A variant (rs150914702), also known as c.4575+2G>A in traditional nomenclature, is reported in the literature in multiple individuals affected with chronic pancreatitis (Audrezet 2002, Steiner 2011). This variant is reported in ClinVar (Variation ID: 53155), and is found in the African population with an allele frequency of 0.18% (44/23,984 alleles) in the Genome Aggregation Database. This variant occurs in the 3' untranslated region at a nucleotide that is moderately conserved, but the effect on the poly(a) signal is unknown. Due to limited information, the clinical significance of the c.*2G>A variant is uncertain at this time. References: Audrezet MP et al. Determination of the relative contribution of three genes-the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene-to the etiology of idiopathic chronic pancreatitis. Eur J Hum Genet. 2002 Feb;10(2):100-6. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 Aug;32(8):912-20.
Integrated Genetics/Laboratory Corporation of America RCV001002168 SCV001362319 likely benign not specified 2019-03-08 criteria provided, single submitter clinical testing Variant summary: CFTR c.*2G>A is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.00017 in 276872 control chromosomes, predominantly at a frequency of 0.0018 within the African subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in CFTR causing CFTR-related diseases (0.0018 vs 0.013), allowing no conclusion about variant significance. c.*2G>A has been reported in the literature in individuals affected with idiopathic chronic pancreatitis, chronic obstructive pulmonary disease and CF-like symptoms (Solomon_2016, Steiner_2011, Mutesa_2009, Audrezet_2002). Furthermore, in one of these reports the authors conclude that the variant is "not reported to cause CF" (Solomon_2016). Therefore, these data do not allow any conclusion about variant significance. Co-occurrence with two other pathogenic variants in a specimen from a patient undergoing testing for CF has been observed in our laboratory (CFTR c.1521_1523delCTT, p.Phe508del; CFTR c.2290C>T, p.Arg764X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. In summary, no conclusive evidence supporting a pathogenic outcome has been ascertained over a span of 5 years since its initial classification at our laboratory. Based on the evidence outlined above, the variant was classified as likely benign.

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