Submissions for variant NM_000492.4(CFTR):c.1882G>A (p.Gly628Arg)

dbSNP: rs397508316

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000577750	SCV000924274	pathogenic	Cystic fibrosis	2019-03-11	reviewed by expert panel	research
CFTR-France	RCV000577750	SCV002573597	pathogenic	Cystic fibrosis	2020-03-26	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577750	SCV002600700	likely pathogenic	Cystic fibrosis	2022-10-24	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1882G>A (p.Gly628Arg) 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 allele was found at a frequency of 4.1e-06 in 244320 control chromosomes. c.1882G>A has been reported in the literature as a compound heterozygous genotype with p.F508del in at-least 4 individuals, to include three with Cystic Fibrosis and one with CBAVD (example, Claustres_2000, De Boeck_2005), as a non-informative genotype (second allele/zygosity not specified) in individuals with Cystic Fibrosis (Fanen_1992, Jorissen_1999), and as a homozygous or compound heterozygous complex allele in cis with p.Ser1235Arg (c.[1882G>A;3705T>G]) (p.[Gly628Arg;Ser1235Arg]) in individuals with Cystic Fibrosis (example, Mercier_1995, Sanchez_2016). The compound heterozygote with the complex allele carried c.946delT on the other allele (Sanchez_2016). At-least one study provides evidences against the pathogenicity of the p.Ser1235Arg variant suggesting that p.Gly628Arg (this variant) might be causative in settings of CF or CBAVD (example, Rene_2011). These data indicate that the variant in isolation is likely to be associated with disease, although the possibility of incomplete genotyping in the four reported compound heterozygotes in isolation with this variant and p.F508del captured above cannot be entirely ruled out. At least two publications report experimental evidence evaluating an impact on protein function (example, Wei_2000, Billet_2010). The most pronounced variant effect results in defective maturation of the CFTR protein (Billet_2010 and Wei_2000). This is consistent with the finding(s) of reduced/defective CFTR channel activity measured as whole cell currents in both these studies. However, in one of these reports, the authors suggest caution with the interpretation of these electrophysiological data due to a lack of confirmation of these observations at the level of single channel measurements. Whole cell currents do not always correlate with single channel activities of CFTR proteins, and are dependent on the number of chloride channels present in the cell membrane. In particular, the double mutant Gly628Arg/Ser1235Arg induced a significantly lower cAMP dependent chloride transport activity (0.11 uA) than Gly628Arg (0.19 uA) or Ser1235Arg (0.39 uA) CFTR alone (Wei_2000). Two clinical diagnostic laboratories, an expert panel (CFTR2) and a database (CFTR-France) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577750	SCV000678972	not provided	Cystic fibrosis		no assertion provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000577750	SCV000692324	likely pathogenic	Cystic fibrosis	2015-04-23	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000577750	SCV001460205	pathogenic	Cystic fibrosis	2020-09-16	no assertion criteria provided	clinical testing