Submissions for variant NM_000492.4(CFTR):c.2620-6T>C

gnomAD frequency: 0.00038  dbSNP: rs371315682

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000589355	SCV000342915	uncertain significance	not provided	2016-06-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001358661	SCV000696913	likely benign	not specified	2022-05-23	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2620-6T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. These predictions are corroborated by experimental evidence in a minigene assay, in which the variant was reported to have no impact on splicing (e.g. Leman_2018). The variant allele was found at a frequency of 0.00054 in 251668 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Chronic Pancreatitis Risk (0.00054 vs 0.0063), allowing no conclusion about variant significance. c.2620-6T>C has been reported in the literature in individuals screened for CFTR mutations (e.g. Zhou_2013, Schrijver_2005, Lefterova_2016) without evidence for disease causality, including a report of the variant being found in trans with the common pathogenic p.F508Del mutation in a healthy pregnant woman, suggesting that c.2620-6T>C may be benign or a very mild disease allele (e.g.Wallerstein_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as benign/likely benign (n=3) and uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000589355	SCV000780897	uncertain significance	not provided	2018-03-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000987963	SCV001137484	likely benign	Cystic fibrosis	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000987963	SCV001722082	benign	Cystic fibrosis	2023-12-31	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000987963	SCV001822113	likely benign	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001588876	SCV001822114	uncertain significance	Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-07-22	criteria provided, single submitter	clinical testing
CFTR-France	RCV000987963	SCV002573596	benign	Cystic fibrosis	2021-01-11	criteria provided, single submitter	curation	the variant does not result in CFTR-RD neither
Ambry Genetics	RCV000987963	SCV002740789	uncertain significance	Cystic fibrosis	2024-03-04	criteria provided, single submitter	clinical testing	The c.2620-6T>C intronic variant results (also known as 2752-6T>C) from a T to C substitution 6 nucleotides upstream from coding exon 16 in the CFTR gene. This variant was identified in a cohort of Hispanic individuals with clinical symptoms of cystic fibrosis; however, complete genotype and phenotype information was not provided (Schrijver I et al. J Mol Diagn, 2005 May;7:289-99). In addition, this variant was identified in a healthy adult African American female in trans with p.F508del (Wallerstein VI et al. Case Rep Genet, 2017 Jan;2017:7281023). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this splice acceptor site; however, direct evidence is unavailable. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000589355	SCV001741502	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000589355	SCV001965635	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004542716	SCV004774616	likely benign	CFTR-related disorder	2023-06-28	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).