Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mendelics | RCV000757881 | SCV000886399 | likely pathogenic | Cystic fibrosis | 2024-05-23 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV001004292 | SCV001163168 | likely pathogenic | Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation | criteria provided, single submitter | clinical testing | ||
| Ambry Genetics | RCV000757881 | SCV002605993 | likely pathogenic | Cystic fibrosis | 2015-07-14 | criteria provided, single submitter | clinical testing | The p.T1036I variant (also known as c.3107C>T), located in coding exon 19 of the CFTR gene, results from a C to T substitution at nucleotide position 3107. The threonine at codon 1036 is replaced by isoleucine, an amino acid with similar properties. This variant was reportedly detected in a patient who was compound heterozygous for the deltaF508 pathogenic mutation (Alibakhshi R, J. Cyst. Fibros. 2008 Mar; 7(2):102-9). A second CF patient was reported to be heterozygous for this variant, however no information was provided about additional CFTR mutations in this individual (Sahami A, J Reprod Infertil 2014 Jan; 15(1):49-56). Additionally, a patient with classic CF was determined to be homozygous for a different missense mutation (p.T1036N; c.3107C>A) at this locus (McGinniss MJ, Hum. Genet. 2005 Dec; 118(3-4):331-8). 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. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. 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. |
| Labcorp Genetics |
RCV000757881 | SCV003470038 | pathogenic | Cystic fibrosis | 2023-08-31 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with cystic fibrosis (PMID: 17662673, 22892530, 24696795, 32442342). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1036 of the CFTR protein (p.Thr1036Ile). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 618964). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CFTR protein function. This variant disrupts the p.Thr1036 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16189704, 27214204, 32429104; 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000757881 | SCV003934572 | likely pathogenic | Cystic fibrosis | 2024-06-13 | criteria provided, single submitter | clinical testing | Variant summary: CFTR c.3107C>T (p.Thr1036Ile) 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 250950 control chromosomes (gnomAD). c.3107C>T has been reported in the literature as a biallelic genotype in individuals affected with Cystic Fibrosis (e.g. Alibakhshi_2008, Sobczynska-Tomaszewska_2013, Zybert_2020) and in one heterozygous individual for which a second allele was not identified (Sahami_2014). A different variant affecting the same codon has been classified as pathogenic by our lab (c.3107C>A, p.Thr1036Asn), supporting the critical relevance of codon 1036 to CFTR protein function. 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: 17662673, 22892530, 24696795, 32442342). ClinVar contains an entry for this variant (Variation ID: 618964). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV003472279 | SCV004213286 | likely pathogenic | Bronchiectasis with or without elevated sweat chloride 1 | 2023-10-18 | criteria provided, single submitter | clinical testing |