Submissions for variant NM_000492.4(CFTR):c.3285A>T (p.Thr1095=)

gnomAD frequency: 0.00570  dbSNP: rs1800118

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000215556	SCV000227628	benign	not specified	2015-12-21	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000215556	SCV000268872	benign	not specified	2013-02-21	criteria provided, single submitter	clinical testing	Thr1095Thr in exon 20 of CFTR: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 0.7% (57/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs1800118).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232081	SCV000285003	benign	Cystic fibrosis	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001095258	SCV000466522	uncertain significance	CFTR-related disorder	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586681	SCV000603000	benign	not provided	2023-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586681	SCV000696963	benign	not provided	2017-05-04	criteria provided, single submitter	clinical testing	Variant summary: This silent variant CFTR c.3285A>T (p.Thr1095Thr), alternatively known as 3417A>T, is located at a non-conserved position in exon 20 of CFTR and it is 82 nucleotides upstream to the nearest exon-intron junction. The variant is not predicted to impact splicing by 5/5 splice prediction tools. ESEfinder predicts the loss of a SC35 binding motif and Mutation Taster predicts as disease-causing. However, predictions from in silico tools are not definitive. There are no experimental in vitro or in vivo functional studies reported for the variant at this time. It has been observed in patients with infertility (non-obstructive infertility, oligoasthenoteratozoospermia and oligoasthenoteratozoospermia), pancreatitis, sarcoidosis, bronchiectasis and COPD. While CFTR mutations may represent a risk factor for these phenotypes, there is a lack of conclusive evidence. Multiple studies have reported this variant to occur in controls and patients at similar frequencies, suggesting that this variant is unlikely to be a risk allele. There are two reports in which this variant was found with CFin 1 German family and in 1 patient referred to CF testing. However, in both studies, cosegregation and/or co-occurrence information is not provided and authors refer to this variant as a polymorphism. This variant was found in 590/124728 control chromosomes (2 homozygotes) including ExAC at an allele frequency of 0.0047303, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This population frequency supports benign outcome for phenotypes other than CF and CBAVD. Most publications spanning over a decade (1994-2009) report this variant as a polymorphism (Ravnik-Glavac 2001, Gallati 2009, Dork 1994, Tzetis 2001, Shackelton 1994). Multiple clinical laboratories/reputable database have classified this variant as likely benign/benign. Taken together, this variant is classified as 'Benign'.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586681	SCV000888083	benign	not provided	2021-02-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586681	SCV001155241	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	CFTR: BP4, BP7, BS2
Johns Hopkins Genomics, Johns Hopkins University	RCV000232081	SCV001167223	benign	Cystic fibrosis	2019-08-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000232081	SCV001181052	likely benign	Cystic fibrosis	2015-01-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genome-Nilou Lab	RCV000232081	SCV001653481	likely benign	Cystic fibrosis	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000586681	SCV001785783	likely benign	not provided	2020-09-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16251901, 23378595, 7515303, 15536480, 7525450, 16128988, 11354633, 11788091, 10601093)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000232081	SCV002507397	likely benign	Cystic fibrosis	2020-03-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257477	SCV002529713	likely benign	Hereditary pancreatitis	2021-04-13	criteria provided, single submitter	curation
Institute of Human Genetics, University of Leipzig Medical Center	RCV000232081	SCV002574032	likely benign	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: BS2, BP4, BP7
PreventionGenetics, part of Exact Sciences	RCV001095258	SCV000304488	likely benign	CFTR-related disorder	2023-03-01	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000215556	SCV001955246	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000586681	SCV001975581	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000586681	SCV002036061	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001095258	SCV002083624	likely benign	CFTR-related disorder	2017-03-28	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001095258	SCV002507481	likely benign	CFTR-related disorder	2020-03-05	no assertion criteria provided	clinical testing