Submissions for variant NM_000492.4(CFTR):c.2210C>T (p.Ser737Phe)

gnomAD frequency: 0.00001  dbSNP: rs186089140

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001369922	SCV001566380	pathogenic	Cystic fibrosis	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 737 of the CFTR protein (p.Ser737Phe). This variant is present in population databases (rs186089140, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 26471113, 26500004, 29298718, 32630227). ClinVar contains an entry for this variant (Variation ID: 53454). 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 not expected to disrupt CFTR protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 9252549). For these reasons, this variant has been classified as Pathogenic.
Suma Genomics	RCV001369922	SCV001847729	uncertain significance	Cystic fibrosis		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001369922	SCV002027442	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001369922	SCV002573998	likely pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 3 unrelated patients 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: PS3_SUP, PM2_SUP, PM3_STR, PP3, PP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001369922	SCV002598637	likely pathogenic	Cystic fibrosis	2023-09-13	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2210C>T (p.Ser737Phe) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251178 control chromosomes.c.2210C>T has been reported in the literature as a homozygous or compound heterozygous genotype in individuals mainly presenting with hypochloremic alkalosis in childhood, mild CF phenotype in teenage years and some residual CFTR function (Terlizi_2018) and at least two additional compound heterozygous individuals identified in a newborn screening have been reclassified with a CF diagnosis reporting elevated sweat chloride tests (Terlizzi_2019, Terlizzi_2021). It has also been reported in cases of pancreatitis/CFTR testing as a non-informative case (second allele/genotype not specified) or as a subsequent non-primary citation (example, Audrezet_2008, Poulou_2012, Masson_2013, Pepermans_2016, Poli_2019, Pankow_2019, Tacetti_2020). A recent report has listed this variant among those that may not respond to CFTR modulators as expected despite its FDA approval (Raraigh_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18687795, 23951356, 30600261, 26500004, 31328366, 22326559, 35527187, 32630227, 29298718, 31005549, 33883100). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely pathogenic (n=1) and VUS (n=3). Some submitters cite overlapping, but not identical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV001369922	SCV002729596	uncertain significance	Cystic fibrosis	2022-02-28	criteria provided, single submitter	clinical testing	The p.S737F variant (also known as c.2210C>T), located in coding exon 14 of the CFTR gene, results from a C to T substitution at nucleotide position 2210. The serine at codon 737 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant has been identified in several individuals with a second CFTR variant and intermediate sweat chloride levels; however, phase information was not provided (Sermet-Gaudelus I et al. Am. J. Respir. Crit. Care Med., 2010 Oct;182:929-36; Pepermans X et al. Clin. Biochem., 2016 Jan;49:154-60; Terlizzi V et al. Ital J Pediatr, 2018 Jan;44:2). This variant was identified in the homozygous state in one infant with intermediate sweat chloride levels and in conjunction with a gross deletion (phase not provided) in an infant with elevated sweat chloride levels; both infants presented with hypochloremic alkalosis (Terlizzi V et al. Ital J Pediatr, 2018 Jan;44:2). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003466904	SCV004215775	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-11-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998161	SCV005625706	likely pathogenic	not provided	2024-10-08	criteria provided, single submitter	clinical testing	The CFTR c.2210C>T (p.Ser737Phe) variant has been reported in the published literature in individuals with cystic fibrosis (PMIDs: 26500004 (2016), 29298718 (2018), and 33883100 (2021)). It has also been reported in individuals with idiopathic chronic pancreatitis (PMIDs: 18687795 (2008) and 23951356 (2013)). The frequency of this variant in the general population, 0.000026 (3/113572 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, this variant is classified as likely pathogenic.