Submissions for variant NM_000492.4(CFTR):c.2057C>A (p.Ser686Tyr)

gnomAD frequency: 0.00005  dbSNP: rs201444561

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665258	SCV000789349	uncertain significance	Cystic fibrosis	2017-01-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000665258	SCV000886360	uncertain significance	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780141	SCV000917186	uncertain significance	not specified	2023-10-02	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2057C>A (p.Ser686Tyr) 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 7.2e-05 in 248868 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (7.2e-05 vs 0.013), allowing no conclusion about variant significance. The variant, c.2057C>A, has been reported in the literature in a patient affected with primary sclerosing cholangitis (Sheth_2003), and with pancreatic ductal adenocarcinoma (Zimmermann_2021). The variant was also reported in an individual affected with asthenospermia (Sickkids database), and cystic fibrosis (da Silva Filho_2020), however, no other variants in trans were specified. In addition, the variant was reported without providing an exact clinical phenotype in homozygous state in an individual of Ashkenazi Jewish origin (Schwartz_2009), and in two individuals who also carried other (potentially) causative CFTR variants (phase not specified) (Zhou_2013, Sontag_2016). On the other hand, the variant was found in two asymptomatic compound heterozygotes, with the pathogenic c.1521_1523del (F508del) variant in trans (Claustres_2017). These reports 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. The following publications have been ascertained in the context of this evaluation (PMID: 28603918, 15784035, 25735457, 19324992, 12783301, 27131402, 23503723, 33747920, 32819855). Severn ClinVar submitters have assessed the variant since 2014, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV000665258	SCV001174947	uncertain significance	Cystic fibrosis	2022-02-03	criteria provided, single submitter	clinical testing	The p.S686Y variant (also known as c.2057C>A), located in coding exon 14 of the CFTR gene, results from a C to A substitution at nucleotide position 2057. The serine at codon 686 is replaced by tyrosine, an amino acid with dissimilar properties. This variant was identified in an individual with primary sclerosing cholangitis (Sheth S et al. Hum. Genet., 2003 Aug;113:286-92). This alteration was also identified in the homozygous state in an individual of Ashkenazi Jewish origin; however, clinical information was not provided (Schwartz KM et al. J Mol Diagn, 2009 May;11:211-5). In addition, this variant was detected in conjunction with other CFTR variants; however, detailed clinical or phase information was not provided (Zhou L et al. Clin. Chem., 2013 Jul;59:1052-61; Sontag MK et al. J. Pediatr., 2016 08;175:150-158.e1). In one study, this variant was identified in two asymptomatic carriers in conjunction with p.F508del (Claustres M et al. Hum. Mutat., 2017 10;38:1297-1315). This amino acid position is well 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.
Illumina Laboratory Services, Illumina	RCV001163687	SCV001325750	uncertain significance	CFTR-related disorders	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.
Genome-Nilou Lab	RCV000665258	SCV002027437	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Invitae	RCV000665258	SCV003263368	uncertain significance	Cystic fibrosis	2022-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 686 of the CFTR protein (p.Ser686Tyr). This variant is present in population databases (rs201444561, gnomAD 0.07%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 27131402). ClinVar contains an entry for this variant (Variation ID: 550500). 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. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV003480750	SCV004224076	uncertain significance	not provided	2022-09-20	criteria provided, single submitter	clinical testing	PP3
Natera, Inc.	RCV001163687	SCV002080705	uncertain significance	CFTR-related disorders	2018-05-26	no assertion criteria provided	clinical testing