Submissions for variant NM_000492.4(CFTR):c.3274T>C (p.Tyr1092His)

gnomAD frequency: 0.00011  dbSNP: rs376968326

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293419	SCV000696961	uncertain significance	not specified	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3274T>C (p.Tyr1092His) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251172 control chromosomes (gnomAD). c.3274T>C has been reported in the literature in individuals affected with Cystic Fibrosis in compound heterozygosity with known- or likely pathogenic variants (Trujillano_2013, Prontera_2016). These data indicate that the variant may 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: 26990548, 34140271, 35273129, 11504857, 27728908, 25735457, 25087612, 23687349). Eleven ClinVar submitters have assessed the variant since 2014: all have classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Eurofins Ntd Llc (ga)	RCV000588214	SCV000859316	uncertain significance	not provided	2018-01-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779527	SCV000916187	uncertain significance	Cystic fibrosis	2018-10-14	criteria provided, single submitter	clinical testing	The CFTR c.3274T>C (p.Tyr1092His) missense variant has been identified in a compound heterozygous state with a second variant in one individual with cystic fibrosis (Trujillano et al. 2013). Control data are unavailable for this variant which is reported at a frequency of 0.000063 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the limited evidence, the p.Tyr1092His variant is classified as a variant of unknown significance but suspicious for pathogenicity for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000779527	SCV000937857	likely pathogenic	Cystic fibrosis	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 1092 of the CFTR protein (p.Tyr1092His). This variant is present in population databases (rs376968326, gnomAD 0.006%). This missense change has been observed in individuals with cystic fibrosis (PMID: 23687349, 27728908, 35273129). ClinVar contains an entry for this variant (Variation ID: 495930). 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 with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588214	SCV001472777	uncertain significance	not provided	2021-01-14	criteria provided, single submitter	clinical testing	The CFTR c.3274T>C; p.Tyr1092His variant (rs376968326) is reported in the literature in the compound heterozygous state with a known pathogenic variant in individuals affected with cystic fibrosis (Prontera 2016, Trujillano 2013). This variant is reported in ClinVar (Variation ID: 495930), and is only observed on seven alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The tyrosine at codon 1092 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the limited clinical data and lack of functional data, the significance of the p.Tyr1092His variant is uncertain at this time. References: Prontera P et al. A Clinical and Molecular Survey of 62 Cystic Fibrosis Patients from Umbria (Central Italy) Disclosing a High Frequency (2.4%) of the 2184insA Allele: Implications for Screening. Public Health Genomics. 2016;19(6):336-341. Trujillano D et al. Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR. J Med Genet. 2013;50(7):455-462.
Mayo Clinic Laboratories, Mayo Clinic	RCV000588214	SCV001714250	uncertain significance	not provided	2020-12-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000588214	SCV001780144	uncertain significance	not provided	2020-02-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed with a pathogenic variant in an individual with cystic fibrosis in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Prontera 2016); This variant is associated with the following publications: (PMID: 23687349, 27728908, 25087612)
Genome-Nilou Lab	RCV000779527	SCV001781365	uncertain significance	Cystic fibrosis	2021-07-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000779527	SCV002606476	uncertain significance	Cystic fibrosis	2022-10-21	criteria provided, single submitter	clinical testing	The p.Y1092H variant (also known as c.3274T>C), located in coding exon 20 of the CFTR gene, results from a T to C substitution at nucleotide position 3274. The tyrosine at codon 1092 is replaced by histidine, an amino acid with similar properties. This variant has been reported in one individual from a cystic fibrosis (CF) cohort in conjunction with an intronic CFTR deletion and in a second CF cohort in an individual in conjunction with the CFTR p.F508del mutation; however, information regarding phase was not provided and clinical details were limited (Trujillano D et al. J. Med. Genet., 2013 Jul;50:455-62; Prontera P et al. Public Health Genomics, 2016 Oct;19:336-341). This variant has also been detected in an exome cohort with limited clinical details provided (Tabor HK et al. Am. J. Hum. Genet., 2014 Aug;95:183-93). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002476275	SCV002789879	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2022-05-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001829623	SCV004118129	uncertain significance	CFTR-related disorder	2022-12-14	criteria provided, single submitter	clinical testing	The CFTR c.3274T>C variant is predicted to result in the amino acid substitution p.Tyr1092His. This variant has been reported in two patients with cystic fibrosis (Table S3, Trujillano et al. 2013. PubMed ID: 23687349; Table 1, Prontera et al. 2016. PubMed ID: 27728908) and in one patient with bronchiectasis (https://www.redalyc.org/journal/6357/635766604013/html/). This variant was also found in a patient with unknown phenotype as part of a newborn screening program (Tabor et al. 2014. PubMed ID: 25087612). However, no further evidence of its pathogenicity was provided regarding segregation with disease in families or functional data. This variant is reported in 0.0047% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117251769-T-C). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV001829623	SCV002083620	uncertain significance	CFTR-related disorder	2018-06-06	no assertion criteria provided	clinical testing