ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2875del (p.Ala959fs) (rs397508447)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000056373 SCV000071478 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Counsyl RCV000056373 SCV000220800 likely pathogenic Cystic fibrosis 2014-10-14 criteria provided, single submitter literature only
Illumina Clinical Services Laboratory,Illumina RCV000056373 SCV000916184 pathogenic Cystic fibrosis 2018-11-02 criteria provided, single submitter clinical testing The CFTR c.2875delG (p.Ala959HisfsTer9) variant, also referred to in the literature as c.3007delG, results in a frameshift and a premature truncation of the protein. This variant is widely reported in the literature and is classified as a cystic fibrosis (CF)-causing mutation according to the CFTR2 mutation database (www.cftr2.org). The database states the mutation has been observed in 40 CF individuals. Across a selection of the available literature, the p.Ala959HisfsTer9 variant was found in three compound heterozygous CF probands, in seven heterozygous probands with CF or congenital bilateral absence of vas deferens (CBAVD) and in 31 additional proband alleles (Mercier et al. 1994; Claustres et al. 2000; Scotet et al. 2003; des Georges et al. 2004; Dorfman et al. 2010; Sosnay et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project but this is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. Based on the collective evidence and the potential impact of frameshift variants, the p.Ala959HisfsTer9 variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000781227 SCV000919131 pathogenic not specified 2018-07-31 criteria provided, single submitter clinical testing Variant summary: CFTR c.2875delG (p.Ala959HisfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., p.Trp1089X, p.Tyr1092X). The variant allele was found at a frequency of 4.1e-06 in 246118 control chromosomes. c.2875delG has been reported in the literature in multiple individuals affected with Cystic Fibrosis. These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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