Submissions for variant NM_000492.4(CFTR):c.1517T>C (p.Ile506Thr)

gnomAD frequency: 0.00001  dbSNP: rs397508224

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000046330	SCV000074343	pathogenic	Cystic fibrosis	2023-09-08	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 10798368, 10923036, 15698946, 16436643, 16963320, 21184098, 30548586; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1649T>C. ClinVar contains an entry for this variant (Variation ID: 53276). 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. This variant disrupts the p.Ile506 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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. This variant is present in population databases (rs397508224, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 506 of the CFTR protein (p.Ile506Thr).
Counsyl	RCV000046330	SCV000798816	uncertain significance	Cystic fibrosis	2018-03-26	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727671	SCV000854981	likely pathogenic	not provided	2018-07-30	criteria provided, single submitter	clinical testing
CFTR-France	RCV000046330	SCV001169473	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000727671	SCV001450135	pathogenic	not provided	2015-05-29	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000046330	SCV001573142	likely pathogenic	Cystic fibrosis	2021-04-29	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000046330	SCV001822056	likely benign	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000046330	SCV002573954	pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 4 unrelated patients 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: PM1, PM3, PM5_STR, PM2_SUP, PP3, PP4
Ambry Genetics	RCV000046330	SCV002708587	likely pathogenic	Cystic fibrosis	2016-05-04	criteria provided, single submitter	clinical testing	The p.I506T variant (also known as c.1517T>C), located in coding exon 11 of the CFTR gene, results from a T to C substitution at nucleotide position 1517. The isoleucine at codon 506 is replaced by threonine, an amino acid with similar properties. This variant was detected in two cystic fibrosis chromosomes in a Mexican population (Orozco L et al. Hum. Genet. 2000; 106:360-5). In addition, one individual of Iranian descent with a classical presentation of cystic fibrosis was found to be homozygous for this variant (Elahi E et al. J Mol Diagn 2006; 8:119-27). This variant has also been further detected with low frequency in various populations of individuals with cystic fibrosis (Girardet A et al. Clin. Genet. 2007; 72:374-7 and Claustres M et al. Hum. Mutat. 2000; 16:143-56). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046330	SCV004037752	pathogenic	Cystic fibrosis	2023-08-30	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1517T>C (p.Ile506Thr) results in a non-conservative amino acid change located in the first ATP-binding domain (IPR003439) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251270 control chromosomes (gnomAD). The variant c.1517T>C (aka. c.1649T>C) has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Cystic Fibrosis (des Georges_2004, de Becdelievre_2011, Elahi_2006, Petrova_2019, and in the databases of Sickkids, CFTR-France, and UMD). The variant has also been detected in populations of individuals with cystic fibrosis, but without providing genotype details (e.g. Orozco_2000). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15698946, 21184098, 16436643, 30548586, 11484207). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as pathogenic.
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000046330	SCV002754552	likely pathogenic	Cystic fibrosis	2022-10-18	no assertion criteria provided	clinical testing