Submissions for variant NM_000492.4(CFTR):c.2252G>T (p.Arg751Leu)

dbSNP: rs397508357

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224113	SCV000280680	likely pathogenic	not provided	2015-03-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000675114	SCV000800665	uncertain significance	Cystic fibrosis	2018-02-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002669	SCV001160657	uncertain significance	not specified	2019-06-26	criteria provided, single submitter	clinical testing	The CFTR c.2252G>T; p.Arg751Leu variant (rs397508357) is reported in the literature in an individual affected with pancreatic-sufficient cystic fibrosis that also carried the pathogenic p.Phe508del variant (Goubau 2009). In testing performed at ARUP, the p.Arg751Leu variant has also been seen in a newborn with elevated sweat chloride that also carried a nonsense variant in CFTR. This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 751 is moderately conserved and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, given the lack of clinical and functional data, the significance of the p.Arg751Leu variant is uncertain at this time. References: Goubau C et al. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax. 2009 Aug;64(8):683-91.
Genome-Nilou Lab	RCV000675114	SCV001822101	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001589163	SCV001822102	uncertain significance	Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000675114	SCV002929737	uncertain significance	Cystic fibrosis	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 751 of the CFTR protein (p.Arg751Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 19318346, 33296276). ClinVar contains an entry for this variant (Variation ID: 235245). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR function (PMID: 33296276). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV003475048	SCV004213354	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-09-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001002669	SCV004813629	uncertain significance	not specified	2024-10-13	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2252G>T (p.Arg751Leu) results in a non-conservative amino acid change in 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 4e-06 in 249372 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2252G>T has been reported in the literature in individuals affected with Cystic Fibrosis who were reported as compound heterozygous with pathogenic variants (e.g. Goubau_2009, Coffey_2017, Haq_2021). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Haq_2021). The following publications have been ascertained in the context of this evaluation (PMID: 27837951, 19318346, 33296276, 38352056). ClinVar contains an entry for this variant (Variation ID: 235245). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Ambry Genetics	RCV000675114	SCV005035726	uncertain significance	Cystic fibrosis	2023-10-02	criteria provided, single submitter	clinical testing	The p.R751L variant (also known as c.2252G>T), located in coding exon 14 of the CFTR gene, results from a G to T substitution at nucleotide position 2252. The arginine at codon 751 is replaced by leucine, an amino acid with dissimilar properties. This alteration, along with the deltaF508 pathogenic mutation, was described in an individual who presented with pancreatic sufficient cystic fibrosis. However, information if this alteration was in cis or trans with deltaF508 was not available (Goubau C et al. Thorax 2009; 64:683-91). Functional studies demonstrated that this variant is functional and biochemical responses were similar to the wildtype CFTR protein level (Haq IJ et al. Am J Physiol Lung Cell Mol Physiol, 2021 Feb;320:L288-L300). This amino acid position is well 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.