Submissions for variant NM_000492.4(CFTR):c.870-7_870-5del

dbSNP: rs759762840

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506879	SCV000601135	uncertain significance	not specified	2017-03-06	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000506879	SCV000708943	likely benign	not specified	2017-05-30	criteria provided, single submitter	clinical testing
Invitae	RCV000868641	SCV001009998	benign	Cystic fibrosis	2024-01-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000506879	SCV001362682	uncertain significance	not specified	2019-06-18	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.870-7_870-5delTTT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00047 in 248124 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00047 vs 0.013), allowing no conclusion about variant significance. The variant, c.870-7_870-5delTTT, has been reported in the literature in individuals affected with Cystic Fibrosis (Shastri_2008, Kharrazi_2015). 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 once as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance until additional information becomes available.
Ambry Genetics	RCV000868641	SCV002682262	benign	Cystic fibrosis	2023-06-07	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003114635	SCV003800492	uncertain significance	not provided	2022-03-11	criteria provided, single submitter	clinical testing	The CFTR c.870-7_870-5del variant (rs759762840) has been reported in a homozygous state in an individual with predominantly gastrointestinal symptoms associated with CFTR-related disorder, but not classical cystic fibrosis (Shastri 2008). In addition, this variant was found along with a second pathogenic variant in an individual with cystic fibrosis (Kharrazzi 2015). This variant is reported in ClinVar (Variation ID: 439088), and is found in the South Asian population with an allele frequency of 0.38% (117/30664 alleles, 2 homozygotes) in the Genome Aggregation Database. This deletion occurs upstream of the acceptor splice consensus sequence of intron six, and computational analyses (Alamut v.2.11) predict that this variant does not alter splicing. Although the c.870-7_870-5del variant is unlikely to be causative of cystic fibrosis, its clinical significance in CFTR-related disorders cannot be determined with certainty. References: Kharrazi M et al. Newborn Screening for Cystic Fibrosis in California. Pediatrics. 2015 Dec;136(6):1062-72. PMID: 26574590. Shastri S et al. Characterisation of mutations and genotype-phenotype correlation in cystic fibrosis: experience from India. J Cyst Fibros. 2008; 7(2):110-5. PMID: 17716958
PreventionGenetics, part of Exact Sciences	RCV004541577	SCV004764732	likely benign	CFTR-related disorder	2023-12-07	criteria provided, single submitter	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).