Submissions for variant NM_000492.4(CFTR):c.165-3C>T

gnomAD frequency: 0.00002  dbSNP: rs200337193

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000046385	SCV000924237	uncertain significance	Cystic fibrosis	2020-01-10	reviewed by expert panel	research
Counsyl	RCV000046385	SCV000220698	likely pathogenic	Cystic fibrosis	2014-09-17	criteria provided, single submitter	literature only
Baylor Genetics	RCV001004227	SCV001163103	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV001009538	SCV001169633	pathogenic	Cystic fibrosis; CFTR-related disorder	2015-07-01	criteria provided, single submitter	curation	the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both
Ambry Genetics	RCV000046385	SCV001173070	likely pathogenic	Cystic fibrosis	2023-10-25	criteria provided, single submitter	clinical testing	The c.165-3C>T intronic variant results from a C to T substitution 3 nucleotides upstream from coding exon 3 in the CFTR gene. This variant was detected in conjunction with a second CFTR alteration in a 44-year-old woman with cystic fibrosis who presented with elevated sweat chloride levels, pulmonary symptoms, and pancreatic sufficiency; however, the pathogenicity of the second alteration was uncertain (Bienvenu T et al. Hum. Genet., 1994 Jul;94:65-8). This alteration was also reported in a fetus with meconium ileus who had p.F508del (Oca F et al. Clin. Chem., 2009 Dec;55:2214-7). In addition, functional studies showed that the variant results in skipping of exon 3 (Bienvenu T et al. Hum. Genet., 1994 Jul;94:65-8; Leman R et al. Nucleic Acids Res, 2018 Sep;46:7913-7923; Joynt AT et al. PLoS Genet, 2020 Oct;16:e1009100). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046385	SCV001338125	likely pathogenic	Cystic fibrosis	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.165-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 3 acceptor site. Several functional studies report this variant affects mRNA splicing and results in exon 3 skipping (Bienvenu_1994, Leman_2018, Joynt_2020). The variant allele was found at a frequency of 2.4e-05 in 250574 control chromosomes (gnomAD). c.165-3C>T has been reported in the literature in individuals affected with Cystic Fibrosis (e.g. Bienvenu_1994, Oca_2009, Kharrazi_2015). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 10923036, 19833837, 7550227, 10982968, 7518409, 8947061, 25087612, 26574590, 29750258, 16617247, 32126153, 31036917, 32256364, 33085659, 34996830, 34196078). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=1) and likely pathogenic (n=3) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046385	SCV002267945	likely pathogenic	Cystic fibrosis	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change falls in intron 2 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs200337193, gnomAD 0.005%). This variant has been observed in individual(s) with cystic fibrosis (PMID: 19833837). This variant is also known as 297-3C>T. ClinVar contains an entry for this variant (Variation ID: 53317). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3 and introduces a premature termination codon (PMID: 7518409). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV003233099	SCV003930979	likely pathogenic	not provided	2023-06-09	criteria provided, single submitter	clinical testing	Classified as a variant of uncertain significance in a well curated database (CFTR2); Published functional studies demonstrate abnormal splicing resulting in aberrant transcript lacking exon 3 as well as some residual full-length transcript (Leman et al., 2018; Joynt et al., 2020); A different variant at this position, c.165-3C>A (reported as 297-3C>A), has been identified in an individual with clinical features of cystic fibrosis who also carried a pathogenic CFTR variant (Strandvik et al., 2001); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as 297-3C>T; This variant is associated with the following publications: (PMID: 28603918, 7550227, 7518409, 29750258, 16617247, 31036917, 8947061, 25087612, 19833837, 26574590, 32126153, 10923036, 32256364, 10982968, 34782259, 11788090, 34996830, 33085659)
Baylor Genetics	RCV003473460	SCV004213386	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-30	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000046385	SCV004808191	uncertain significance	Cystic fibrosis	2024-03-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000046385	SCV002583265	likely pathogenic	Cystic fibrosis		no assertion criteria provided	clinical testing