Submissions for variant NM_000492.4(CFTR):c.3849G>C (p.Arg1283Ser)

dbSNP: rs1792935893

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001247277	SCV001420689	uncertain significance	Cystic fibrosis	2021-08-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with serine at codon 1283 of the CFTR protein (p.Arg1283Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with clinical features of cystic fibrosis (PMID: 10462611; Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Arg1283 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 1284468), which suggests that this may be a clinically significant amino acid residue. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331090	SCV004037691	uncertain significance	not specified	2023-08-29	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3849G>C (p.Arg1283Ser) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250894 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3849G>C has been reported in the literature as a compound heterozygous genotype in at least two individuals of African American ancestry with clinical features of Cystic Fibrosis (Wang_1997, Ridge_2013). These data do not allow any strong conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another variant affecting the same amino acid (i.e. p.Arg1283Met) has been reported in association with Cystic Fibrosis in the HGMD database and classified as pathogenic in ClinVar, suggesting Arg1283 may be important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 23343000, 10462611). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Natera, Inc.	RCV001830007	SCV002075894	uncertain significance	CFTR-related disorders	2019-05-03	no assertion criteria provided	clinical testing