ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2909-15T>G (rs397508455)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508198 SCV000601082 likely pathogenic not provided 2017-07-20 criteria provided, single submitter clinical testing
CFTR-France RCV001009391 SCV001169244 pathogenic Cystic fibrosis; CFTR-related disorders 2018-01-29 criteria provided, single submitter curation when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
CeGaT Praxis fuer Humangenetik Tuebingen RCV000508198 SCV001246819 pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000670991 SCV001363802 likely pathogenic Cystic fibrosis 2019-03-04 criteria provided, single submitter clinical testing Variant summary: CFTR c.2909-15T>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. One computational tool predicts a significant impact on normal splicing: the variant creates a 3 intronic acceptor site. Experimental evidence demonstrated the variant to affect mRNA splicing; specifically the variant was found to lead to aberrant splicing in 81.23% of transcripts assessed, resulting in the out-of-frame skipping of exon 16 (Raynal_2013). The variant allele was found at a frequency of 4.1e-06 in 245360 control chromosomes (gnomAD). c.2909-15T>G has been reported in the literature in newborn screening cases associated with Cystic Fibrosis and CFTR-related metabolic syndrome (Baker_2015, Girardet_2007); in one study it was reported in two infants with an initial inconclusive diagnosis of cystic fibrosis without follow-up information provided at older ages (Ooi_2015). c.2909-15T>G was detected in homozygous state in one male affected with congenital bilateral absence of the vas deferens (CBAVD) (Dayangac_2004) and has been described in the literature to be associated with CBAVD and be frequently found in infertile males (Tsui_2013, Li_2012). These data indicate that the variant is likely to be associated with disease. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic (1x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000670991 SCV001485974 uncertain significance Cystic fibrosis 2020-01-24 criteria provided, single submitter clinical testing This sequence change falls in intron 17 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. This variant is present in population databases (rs397508455, ExAC 0.006%). This variant has been observed in individual(s) with congenital bilateral absence of the vas deferens (PMID: 15070876, 23381846). This variant is also known as c.3041+15T>G in the literature. ClinVar contains an entry for this variant (Variation ID: 53592). @@ Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 23381846). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000670991 SCV000795924 uncertain significance Cystic fibrosis 2017-11-30 no assertion criteria provided clinical testing

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