Submissions for variant NM_000492.4(CFTR):c.567C>A (p.Asn189Lys)

dbSNP: rs397508755

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000577311	SCV001186409	likely pathogenic	Cystic fibrosis	2019-11-19	criteria provided, single submitter	clinical testing	The p.N189K variant (also known as c.567C>A), located in coding exon 5 of the CFTR gene, results from a C to A substitution at nucleotide position 567. The asparagine at codon 189 is replaced by lysine, an amino acid with similar properties. This variant was confirmed in trans with a frameshift variant in a Chinese individual with cystic fibrosis (CF) with pulmonary manifestations and elevated sweat chloride levels (Li N et al. Chin. Med. J., 2006 Jan;119:103-9). In a cohort of Chinese individuals with CF, this variant was detected in 4 of 22 individuals (Zheng B et al. Pediatr. Pulmonol., 2017 03;52:E11-E14). This variant was not reported in the gnomAD database, with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000577311	SCV002573984	uncertain significance	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: PM3, PM2_SUP, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700333	SCV005203754	uncertain significance	not specified	2024-07-03	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.567C>A (p.Asn189Lys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 250352 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.567C>A has been reported in the literature as a biallelic compound heterozygous genotype in at-least one Chinese individual affected with Cystic Fibrosis and continues to be cited by others (example, Li_2006 cited in Zheng_2017, Shen_2022, Zacarias_2023). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 54002). Based on the evidence outlined above, the variant was classified as uncertain significance.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577311	SCV000679168	not provided	Cystic fibrosis		no assertion provided	literature only