Submissions for variant NM_000492.3(CFTR):c.164+1G>T (rs397508243)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000576651	SCV000677597	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Counsyl	RCV000576651	SCV000796986	pathogenic	Cystic fibrosis	2018-01-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000576651	SCV001363799	pathogenic	Cystic fibrosis	2019-06-10	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.164+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. One predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249608 control chromosomes (gnomAD). The variant, c.164+1G>T, has been reported in the literature in individuals affected with Cystic Fibrosis, idiopathic chronic pancreatitis or bronchiectasis (Estivill_1997, Audrezet_2008, Dorfman_2010, Pagin_2016, Sapiejka_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000576651	SCV001574870	likely pathogenic	Cystic fibrosis	2018-08-30	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the CFTR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of cystic fibrosis (PMID: 26900683, 20059485). ClinVar contains an entry for this variant (Variation ID: 53305). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). 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.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000576651	SCV000679329	not provided	Cystic fibrosis		no assertion provided	literature only