Submissions for variant NM_000492.4(CFTR):c.374T>C (p.Ile125Thr)

gnomAD frequency: 0.00026  dbSNP: rs141723617

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081823	SCV000074982	likely benign	Cystic fibrosis	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000595646	SCV000696986	likely benign	not specified	2022-01-15	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.374T>C (p.Ile125Thr) results in a non-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 0.00074 in 252614 control chromosomes, predominantly at a frequency of 0.0094 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis allowing no conclusion about variant significance. c.374T>C has been reported in the literature in sequencing studies of healthy controls and individuals affected with Cystic Fibrosis, pancreatitis of idiopathic, chronic, acute and autoimmume etiologies, and as a VUS reported in settings of carrier screening (example, Kilinc_2002, Chang_2007, Kim_2010, Ngiam_2006, Jang_2013, Nakano_2015, Chang_2015, Lee_2003, DeWachter_2017, Archibald_2017, Xiao_2017, Guan_2018, Schrijver_2016). Specifically, this variant was reported in trans with p.F508del in a female patient of Chinese ethnicity who was reportedly pancreatic sufficient and had sweat chloride of < 60 mmol/L (36mmol/L) (DeWachter_2017). These report(s) 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. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=3; benign, n=1; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Eurofins Ntd Llc (ga)	RCV000595646	SCV000706922	likely benign	not specified	2017-03-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001509309	SCV000885191	uncertain significance	not provided	2023-03-22	criteria provided, single submitter	clinical testing	The CFTR c.374T>C; p.Ile125Thr variant (rs141723617) is reported in the literature in the heterozygous state in individuals affected with cystic fibrosis or CFTR-related disorders such as bronchiectasis and pancreatitis, but its clinical significance was not determined (Chang 2007, Kilinc 2002, Lee 2003, Nakano 2015, Ngiam 2006, Zhang 2022). This variant is listed in ClinVar (Variation ID: 53802), and is found in the East Asian population with an allele frequency of 0.96% (192/19944 alleles, including a single homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.668). However, given the limited clinical and lack of functional data, the significance of the p.Ile125Thr variant is uncertain at this time. References: Chang M et al. Spectrum of mutations and variants/haplotypes of CFTR and genotype-phenotype correlation in idiopathic chronic pancreatitis and controls in Chinese by complete analysis. Clin Genet. 2007; 71(6):530-9. PMID: 17539902. Kilinc MO et al. Highest heterogeneity for cystic fibrosis: 36 mutations account for 75% of all CF chromosomes in Turkish patients. Am J Med Genet. 2002 Dec 1;113(3):250-7. PMID: 12439892. Lee K et al. Mutation analysis of SPINK1 and CFTR gene in Korean patients with alcoholic chronic pancreatitis. Dig Dis Sci. 2005; 50(10):1852-6. PMID: 16187186. Nakano E et al. Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis. Dig Dis Sci. 2015; 60(5):1297-307. PMID: 25492507. Ngiam N et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asians with chronic pulmonary disease: a pilot study. J Cyst Fibros. 2006; 5(3):159-64. PMID: 16678503. Zhang N et al. Clinical and gene mutation features of cystic fibrosis: an analysis of 8 cases]. Zhongguo Dang Dai Er Ke Za Zhi. 2022 Jul 15;24(7):771-777. Chinese. PMID: 35894192.
Ambry Genetics	RCV001081823	SCV001182605	likely benign	Cystic fibrosis	2018-04-18	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	RCV001163272	SCV001325295	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001509309	SCV001715935	uncertain significance	not provided	2023-05-16	criteria provided, single submitter	clinical testing	BS2
Genome-Nilou Lab	RCV001081823	SCV001821996	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001509309	SCV002046709	uncertain significance	not provided	2023-07-25	criteria provided, single submitter	clinical testing	The CFTR c.374T>C (p.Ile125Thr) variant has been reported in the published literature in individuals with cystic fibrosis ((PMID: 12439892 (2002), 26437683 (2015)), pancreatitis (PMID: 12952861 (2003), 25492507 (2015), 25869325 (2015), 29173301 (2017)), bronchiectasis (PMID: 12952861 (2003), 16678503 (2006), 29997923 (2018)) as well as in healthy individuals (PMID: 12952861 (2003), 16678503 (2006), 16778407 (2006), 29997923 (2018)). The frequency of this variant in the general population, 0.011 (155/14424 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Revvity Omics, Revvity	RCV001509309	SCV003831640	uncertain significance	not provided	2022-01-29	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001081823	SCV001453947	benign	Cystic fibrosis	2020-04-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001163272	SCV004724100	likely benign	CFTR-related disorder	2019-06-17	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).