ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2770G>A (p.Asp924Asn) (rs201759207)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV001255211 SCV000696923 uncertain significance not specified 2020-08-03 criteria provided, single submitter clinical testing Variant summary: CFTR c.2770G>A (p.Asp924Asn) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, in a minigene assay this variant has been shown to cause exon skipping (Baatallah_2018). The variant allele was found at a frequency of 6.8e-05 in 251412 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (6.8e-05 vs 0.013), allowing no conclusion about variant significance. c.2770G>A has been reported in the literature in individuals affected with Cystic Fibrosis (CF), CF- related disorders as well as pancreatic cancer (e.g. Alonso_2007, deCid_2010, Koyano_2010, Zietkiewicz_2013, Guan_2018, Tamura_2019, Claustres_2017). These reports however, do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. CFTR2 database also report this variant as variant of uncertain significance. Four other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587040 SCV000704123 uncertain significance not provided 2016-12-05 criteria provided, single submitter clinical testing
Counsyl RCV000577296 SCV000796009 uncertain significance Cystic fibrosis 2017-11-27 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000587040 SCV000883572 uncertain significance not provided 2017-06-27 criteria provided, single submitter clinical testing The CFTR c.2770G>A; p.Asp924Asn variant (rs201759207) has been reported in cystic fibrosis patients, but its clinical significance was not determined (Alonso 2006, Zietkiewicz 2014). It is listed in ClinVar (Variation ID: 53565) and observed in the general population at an overall frequency of 0.009% (25/277152 alleles) in the Genome Aggregation Database. The aspartic acid at codon 924 is highly conserved, but computational algorithms (PolyPhen-2: probably damaging; SIFT: tolerated) are inconclusive on the variant's impact on the protein. Due to the limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Alonso M et al. Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry. Ann Hum Genet. 2007; 71(Pt 2):194-201. Zietkiewicz E et al. CFTR mutations spectrum and the efficiency of molecular diagnostics in Polish cystic fibrosis patients. PLoS One. 2014; 9(2):e89094.
Ambry Genetics RCV001016547 SCV001177512 uncertain significance Inborn genetic diseases 2018-06-14 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577296 SCV000679359 not provided Cystic fibrosis no assertion provided literature only

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