Submissions for variant NM_000492.4(CFTR):c.2738A>G (p.Tyr913Cys)

gnomAD frequency: 0.00001  dbSNP: rs121909008

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001004485	SCV001163530	likely pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007548	SCV001581776	pathogenic	Cystic fibrosis	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 913 of the CFTR protein (p.Tyr913Cys). This variant is present in population databases (rs121909008, gnomAD 0.007%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 2210768, 18766277, 28830496). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 2870A>G. ClinVar contains an entry for this variant (Variation ID: 7128). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007548	SCV002041568	pathogenic	Cystic fibrosis	2021-11-23	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2738A>G (p.Tyr913Cys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. This variant is lines the channel-pore as it is present in the eighth of the CFTR's 12 membrane spanning segments (TM8) (Negoda_2019). 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 4e-06 in 251450 control chromosomes. c.2738A>G has been reported in the literature as a compound heterozygous genotype or without a second allele specified in multiple individuals affected with Classic Cystic Fibrosis (example, Vidaud_1990, Gasparini_1991, Macek_1997, VanBiervliet_2007, Claustres_2000, Ramirez_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function using patch-clamp recording and suggest that pore-lining TM8 is among the most important transmembrane segment controlling the permeation phenotype of the CFTR channel, and also that movement of TM8 may be critically involved in channel gating (Negoda_2019). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000007548	SCV002574049	likely pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient 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
Ambry Genetics	RCV000007548	SCV002747777	pathogenic	Cystic fibrosis	2025-03-12	criteria provided, single submitter	clinical testing	The p.Y913C pathogenic mutation (also known as c.2738A>G), located in coding exon 17 of the CFTR gene, results from an A to G substitution at nucleotide position 2738. The tyrosine at codon 913 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was first identified in a French individual diagnosed with cystic fibrosis with p.F508del in trans (Vidaud M et al. Hum. Genet., 1990 Sep;85:446-9). It was also identified in two Belgian individuals diagnosed with cystic fibrosis and elevated sweat chloride levels; both individuals had a second pathogenic CFTR alteration, but phase was not provided (Van Biervliet S et al. Ann. Nutr. Metab., 2007 Jan;51:541-9; De Wachter E et al. Orphanet J Rare Dis, 2017 Aug;12:142). In an assay testing CFTR function, this variant showed a functionally abnormal result (Bihler H et al. J Cyst Fibros, 2024 Jul;23:664-675). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Neuberg Centre For Genomic Medicine, NCGM	RCV000007548	SCV004176545	pathogenic	Cystic fibrosis		criteria provided, single submitter	clinical testing	The missense c.2738A>G(p.Tyr913Cys) variant in CFTR gene has been reported previously in compound heterozygous state in multiple individuals affected with CFTR related disorder (De Wachter E, et. al., 2017; Oller de Ramírez AM, et. al., 2006). Experimental evidence suggests this missense change affects CFTR function (Negoda A et al. 2019). The p.Tyr913Cys variant is present with allele frequency of 0.0004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). Multiple lines of computational evidence (Polyphen - Probably damaging, SIFT – Damaging and Mutation Taster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position on CFTR gene is predicted as conserved by PhyloP across 100 vertebrates. The amino acid Tyr at position 913 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV004566690	SCV005057451	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-01-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031407	SCV005673370	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-04-16	criteria provided, single submitter	clinical testing
OMIM	RCV000007548	SCV000027749	pathogenic	Cystic fibrosis	1990-09-01	no assertion criteria provided	literature only