ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2657+2_2657+3insA (rs397508414)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046646 SCV000074659 pathogenic Cystic fibrosis 2020-09-15 criteria provided, single submitter clinical testing This sequence change falls in intron 16 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs397508414, ExAC 0.003%). This variant has been observed in combination with another CFTR variant in individuals affected with cystic fibrosis (PMID: 18195584, 24586523, 16189704), as well as in individuals with atypical/non-classic CF and/or borderline sweat chloride (PMID: 11101688, 12167682, 23974870, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.2789+2insA in the literature. ClinVar contains an entry for this variant (Variation ID: 53536). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant does not affect mRNA splicing (PMID: 23974870, 25066652). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000790809 SCV000226434 pathogenic not provided 2017-05-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000046646 SCV000696914 likely pathogenic Cystic fibrosis 2016-12-15 criteria provided, single submitter clinical testing Variant summary: The CFTR c.2657+2_2657+3insA variant, alternatively also known as 2789+2insA, is an intronic variant causing insertion of adenine in intron 16 in proximity of the splice donor site. Mutation Taster predicts a damaging outcome for this variant. In addition, 4/5 splice prediction tools predict abrogation of utilization of the splice donor site. Two independent functional studies by minigene assay show that this variant only causes intermediate skipping of exon (i.e. partial exon skipping) (Sosnay_2013, Sharma_2014). Relative amount of properly spliced RNA transcript and fully process protein generated by CFTR minigenes transfected into two human cell lines (HEK and CFBE41o-) were 717.3% and 808.3%, respectively (Sosnay_2013). The exon 16 (residues 874-886) encodes part of ABC transporter transmembrane region and thus its skipping is expected to be deleterious for protein function. In literature, this variant is widely reported as a pathogenic variant and is reported to cause non-classic CF with consistent genotype-phenotype data. In Caucasian CF population in US the variants allele frequency was 0.1% (Schrijver_2016). This variant was found in 2/121402 control chromosomes from ExAC, only observed in the European (Non-Finnish) subpopulation at a frequency of 0.003% (2/66738). Thus, this variant is clearly overrepresented in patient population in comparison to controls in population of European origin, strongly supporting for pathogenicity. One clinical laboratory has classified this variant as pathogenic. Considering all evidences, this variant is currently classified as likely pathogenic.
Mendelics RCV000046646 SCV000886400 uncertain significance Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000046646 SCV000992328 uncertain significance Cystic fibrosis 2019-10-15 criteria provided, single submitter clinical testing CFTR sequence variant of uncertain clinical significance (previously reported for this patient by mass spectrometry genotyping). See www.CFTR2.org for phenotype information.
CFTR-France RCV001009498 SCV001169593 pathogenic CFTR-related disorders 2018-01-29 criteria provided, single submitter curation
GeneDx RCV000790809 SCV001791976 uncertain significance not provided 2020-11-09 criteria provided, single submitter clinical testing Published functional studies are inconclusive: minimal effect on CFTR splicing with generation of correctly spliced CFTR transcript close to wild type levels in two different cell lines; CFTR protein levels comparable to wild type (Sosnay 2013, Sharma 2014); Classified as a variant of unknown significance in a well-curated database (CFTR2); In silico analysis supports a deleterious effect on splicing This variant is associated with the following publications: (PMID: 31036917, 18195584, 23168765, 26014425, 26708955, 33085659, 23974870, 25066652, 31611131, 15754262, 24586523, 27214204, 16189704, 11101688, 20144563, 12000363, 12167682, 31420175)
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000790809 SCV001549042 likely pathogenic not provided no assertion criteria provided clinical testing The CFTR c.2657+2insA variant was identified in multiple cases of cystic fibrosis as well as a obstructive ozoospermia case; in most cases the variant was found as a compound heterozygous variant with the deltaF508Del variant (Zietkiewicz_2014_PMID:24586523, Giacobbe_2012_PMID:23168765; Jezequel_2000_PMID:11101688; Visich_2002_PMID:12000363). The variant was identified in dbSNP (ID: rs397508414), ClinVar (classified as pathogenic by EGL Diagnostics, as likely pathogenic by Integrated Genetics and Invitae, and as uncertain significance by John Hopkins Genomics and Mendelics). The variant was identified in control databases in 18 of 282868 chromosomes at a frequency of 0.00006363 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 17 of 129184 chromosomes (freq: 0.000132) and African in 1 of 24964 chromosomes (freq: 0.00004), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The c.2657+2insA variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict the loss of the canonical 5' splice site. However, functional analysis of this variant using minigene assays revealed minimal effects on splicing (Sharma_2014_PMID:25066652; Sosnay_2013_PMID:23974870). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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