Submissions for variant NM_000492.4(CFTR):c.2758G>T (p.Val920Leu)

dbSNP: rs373885282

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723423	SCV000700346	uncertain significance	not provided	2017-03-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000723423	SCV001334751	uncertain significance	not provided	2020-02-01	criteria provided, single submitter	clinical testing
Institute of Reproductive Genetics, University of Münster	RCV001646981	SCV001860329	pathogenic	Obstructive azoospermia	2022-03-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000577094	SCV002752162	uncertain significance	Cystic fibrosis	2023-05-04	criteria provided, single submitter	clinical testing	The p.V920L variant (also known as c.2758G>T), located in coding exon 17 of the CFTR gene, results from a G to T substitution at nucleotide position 2758. The valine at codon 920 is replaced by leucine, an amino acid with highly similar properties. This variant was identified in conjunction with p.R1162* in an infant with an abnormal newborn screen and negative sweat chloride levels; phase information was not provided (Castellani C et al. Arch. Dis. Child., 2017 07;102:644-646). This variant has been identified in two individuals with bronchiectasis; however, no second pathogenic CFTR variants were identified (Divac A et al. Thorax, 2005 Jan;60:85; Seia M et al. Clin. Biochem., 2009 May;42:611-6). This amino acid position is highly conserved in available species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000577094	SCV002959446	uncertain significance	Cystic fibrosis	2022-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 920 of the CFTR protein (p.Val920Leu). This variant is present in population databases (rs373885282, gnomAD 0.005%). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 15618592, 19318035, 26755536). ClinVar contains an entry for this variant (Variation ID: 53562). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230381	SCV003929022	uncertain significance	not specified	2023-04-13	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2758G>T (p.Val920Leu) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 292466 control chromosomes. c.2758G>T has been reported in the literature in an individuals affected with CBAVD or infertility who carried a second pathogenic variant without confirmation that the variants were in trans (Sickkids database, Rudnik-Schoneborn_2021, Wyrwoll_2022), as well as individuals with conditions related to CF but without a second pathogenic variant identified (e.g. Divac_2005, Seia_2009, Basaran_2019). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=1) or uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577094	SCV000679007	not provided	Cystic fibrosis		no assertion provided	literature only