Submissions for variant NM_000492.4(CFTR):c.3897A>G (p.Thr1299=)

gnomAD frequency: 0.00101  dbSNP: rs1800131

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000150339	SCV000110872	likely benign	not specified	2017-01-11	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150339	SCV000197442	likely benign	not specified	2013-02-21	criteria provided, single submitter	clinical testing	Thr1299Thr in exon 24 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 0.1% (10/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs1800131).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001007581	SCV000260695	benign	Cystic fibrosis	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000150339	SCV000304495	likely benign	not specified		criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590053	SCV000602975	benign	not provided	2023-11-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590053	SCV000696999	benign	not provided	2016-10-24	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.3897A>G (p.Thr1299Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 141/121634 control chromosomes (1 homozygote) at a frequency of 0.0011592, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603), however the homozygous occurrence does suggest a benign role of the variant. In the literature, the variant is reported in both control and patient populations across multiple ethnicities. However, genotypic information of the patients carrying the variant is not clearly specified in publications, and most of them classify it as a 'polymorphism.' One LabCorp specimen carries F508del (DV) and c.1021T>C (DV) (phase of the variants unknown) and the clinical representation of the pt is reported to be CF. In addition, UMD classifies the variant as a polymorphism that is reported in 5 patients (CF or CBAVD), each carrying two other deleterious variants. Although phase of the two deleterious variants is not reported for every patient, UMD cites 2 CF patients that carry p.Lys710X in cis with p.Thr1299Thr. Thus, we have a unequivocal evidence of the presence of deleterious variant(s) in cis with this silent variant in CF patients, suggesting a notion that it is not causally related to these phenotypes and is likely to be a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000150339	SCV000888092	benign	not specified	2022-02-02	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV001007581	SCV001167216	likely benign	Cystic fibrosis	2019-07-06	criteria provided, single submitter	clinical testing
CFTR-France	RCV001007581	SCV001169180	benign	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation	the variant does not result in CFTR-RD neither
Ambry Genetics	RCV001007581	SCV001182989	likely benign	Cystic fibrosis	2023-05-23	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.
Illumina Laboratory Services, Illumina	RCV001158876	SCV001320539	uncertain significance	CFTR-related disorder	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000590053	SCV001501422	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	CFTR: BP4, BP7
Sema4, Sema4	RCV002257405	SCV002529721	likely benign	Hereditary pancreatitis	2021-04-21	criteria provided, single submitter	curation
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000590053	SCV001740109	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000590053	SCV001931256	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000590053	SCV001952772	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000590053	SCV001963662	likely benign	not provided		no assertion criteria provided	clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV001158876	SCV002029153	likely benign	CFTR-related disorder	2021-03-29	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001158876	SCV002075908	likely benign	CFTR-related disorder	2018-03-21	no assertion criteria provided	clinical testing