Submissions for variant NM_000492.4(CFTR):c.1040G>T (p.Arg347Leu)

dbSNP: rs77932196

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001004252	SCV001163128	likely pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000007591	SCV001169459	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007591	SCV002129541	pathogenic	Cystic fibrosis	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 347 of the CFTR protein (p.Arg347Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cystic fibrosis or congenital bilateral absence of the vas deferens (PMID: 10923036). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7171). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. This variant disrupts the p.Arg347 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2344617, 12400067, 21679131, 22020151, 25583415). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000007591	SCV002574019	pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient 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, PM3, PM2_SUP, PM5_STR, PP3, PP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007591	SCV004039143	pathogenic	Cystic fibrosis	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1040G>T (p.Arg347Leu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251126 control chromosomes (gnomAD). c.1040G>T has been reported in the literature in individuals affected with Cystic Fibrosis (examples: Stratton_2012, Hu_2017, Clausters_2000). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 29095814, 10923036, 22787562). Other variants affecting the same codon have been classified pathogenic in ClinVar and internally (CV ID 7182, 7110). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003466829	SCV004215787	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2022-03-14	criteria provided, single submitter	clinical testing
OMIM	RCV000007591	SCV000027792	pathogenic	Cystic fibrosis	2018-04-09	no assertion criteria provided	literature only