ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046646 SCV000074659 pathogenic Cystic fibrosis 2019-11-11 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
Integrated Genetics/Laboratory Corporation of America 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 for phenotype information.
CFTR-France RCV001009498 SCV001169593 pathogenic CFTR-related disorders 2018-01-29 criteria provided, single submitter curation

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