Submissions for variant NM_000492.4(CFTR):c.1210-2A>C

dbSNP: rs397508179

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV001193108	SCV001981569	pathogenic	Cystic fibrosis	2021-09-24	reviewed by expert panel	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001372	SCV001158570	pathogenic	not specified	2019-06-26	criteria provided, single submitter	clinical testing	The CFTR c.1210-2A>C variant (rs397508179), also known as 1342-2A>C for traditional nomenclature, is described in the literature in two siblings affected with CF who were homozygous for the variant, and in another affected individual who carried a nonsense variant on the opposite allele (Dork 1993). The c.1210-2A>C variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical splice acceptor site, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. REFERENCES Dork T et al. Severe splice site mutation preceding exon 9 of the CFTR gene. Hum Mol Genet. 1993 Aug;2(8):1313-4.
Baylor Genetics	RCV001004258	SCV001163134	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193108	SCV001361721	pathogenic	Cystic fibrosis	2019-01-17	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1210-2A>C 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: Five predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. This variant was detected in two Cystic Fibrosis families from Southwest Germany. In the first family, the homozygous twins were 15 months old and pancreas insufficient. In the second family, the affected girl is a compound heterozygote for c.1210-2A>C (legacy name 1342-2 A->C) and Y1092X. She was 13 years old, pancreas insufficient and colonized with P aeruginosa (Sickkids database). The variant was absent in 242414 control chromosomes. A peer-reviewed publication reporting the findings presented in the Sickkids database was not immediately available at the time of this classification. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV002277135	SCV002567563	likely pathogenic	not provided	2022-08-12	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Observed multiple times with a pathogenic variant in patients with cystic fibrosis in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Dork et al., 1993; Terlizzi et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.1342-2A>C; This variant is associated with the following publications: (PMID: 25525159, 35451201, 27488443, 30577776, 7691349)
Johns Hopkins Genomics, Johns Hopkins University	RCV001193108	SCV002570327	pathogenic	Cystic fibrosis	2022-09-06	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001193108	SCV002573804	pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 9 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: PS3_SUP, PM2_SUP, PM3_STR, PM4, PP3, PP4
Natera, Inc.	RCV001826608	SCV002080560	pathogenic	CFTR-related disorder	2018-11-16	no assertion criteria provided	clinical testing