Submissions for variant NM_000492.4(CFTR):c.2195T>G (p.Leu732Ter)

dbSNP: rs397508350

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056360	SCV000071542	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056360	SCV000696889	pathogenic	Cystic fibrosis	2016-06-25	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.2195T>G (p.Leu732X) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation of this variant at Leu732 would eliminate part of the CFTR regulator domain, the N terminal transmembrane domain, the AAA+ ATPase domain, and the P-loop NTPase fold domain. Consequently, one in silico tool predicts a damaging outcome for this variant. This variant was found in 1/120718 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). It was reported in many CF patients with at least one patient being homozygous for the variant, indicating pathogenicity. Furthermore, truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Trp1089X, p.Tyr1092X). Additionally, at least one database classified the variant as pathogenic/CF-causing. Taken together, this variant is classified as pathogenic.
Mendelics	RCV000056360	SCV000886254	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
CFTR-France	RCV000056360	SCV001169545	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269766	SCV001450016	pathogenic	not provided	2018-07-13	criteria provided, single submitter	clinical testing
Invitae	RCV000056360	SCV001580681	pathogenic	Cystic fibrosis	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu732*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs397508350, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with CFTR-related conditions (PMID: 9003508, 23974870). ClinVar contains an entry for this variant (Variation ID: 53451). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000056360	SCV002729463	pathogenic	Cystic fibrosis	2015-07-21	criteria provided, single submitter	clinical testing	The p.L732* pathogenic mutation (also known as c.2195T>G and p.L732X) located in coding exon 14 of the CFTR gene, results from a T to G substitution at nucleotide position 2195. This changes the amino acid from a leucine to a stop codon within coding exon 14. In one study, this mutation was reported in a patient with congenital bilateral absence of the vas deferens (CBAVD) who was heterozygous for the 5T allele and also had recurrent bronchitis and a few gastrointestinal manifestations of CF (Kanavakis E et al. Mol Hum Reprod. 1998;4(4):333-337). In another study, this mutation was seen along with the c.3717+12191C>T (c.3849+10kbC>T) mutation in a patient with failure to thrive, chronic cough, chronic sinusitis, and elevated sweat chloride levels (McGinniss MJ et al. Hum Genet. 2005;118(3-4):331-338). Functional in vitro studies found that cells carrying this pathogenic mutation had elevated sweat chloride levels, pancreatic insufficiency, and decreased lung function (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167, Supplementary Table and The Clinical and Functional Translation of CFTR (CFTR2); available at http://cftr2.org. Accessed May 27, 2015). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, p.L732* is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Baylor Genetics	RCV003473477	SCV004213576	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-01-29	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001269766	SCV004226575	pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing	PP4, PP5, PM2, PM3_very_strong, PVS1
Counsyl	RCV000056360	SCV001132145	pathogenic	Cystic fibrosis	2015-07-28	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001269766	SCV001743002	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001269766	SCV001974092	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001831744	SCV002080720	pathogenic	CFTR-related disorders	2017-03-17	no assertion criteria provided	clinical testing