Submissions for variant NM_000492.4(CFTR):c.164+1G>T

dbSNP: rs397508243

Total submissions: 8

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000576651	SCV001574870	pathogenic	Cystic fibrosis	2024-01-20	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. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 11810271, 26900683). ClinVar contains an entry for this variant (Variation ID: 53305). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000576651	SCV002573835	likely pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 2 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1_MOD, PS1_SUP, PM2_SUP, PM3_STR, PP4
Ambry Genetics	RCV000576651	SCV002709339	likely pathogenic	Cystic fibrosis	2022-06-15	criteria provided, single submitter	clinical testing	The c.164+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 2 of the CFTR gene. This variant was reported in one individual with bronchiectasis with a second CFTR variant; however, phase was not provided (Pagin A et al. PLoS One, 2016 Feb;11:e0149426). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Baylor Genetics	RCV003473459	SCV004213554	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-03-02	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000576651	SCV000679329	not provided	Cystic fibrosis		no assertion provided	literature only