Submissions for variant NM_000492.4(CFTR):c.523A>G (p.Ile175Val)

dbSNP: rs397508744

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000577574	SCV000790951	uncertain significance	Cystic fibrosis	2017-04-17	criteria provided, single submitter	clinical testing
CFTR-France	RCV000577574	SCV001169319	pathogenic	Cystic fibrosis	2015-07-03	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000577574	SCV001822008	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577574	SCV002238808	pathogenic	Cystic fibrosis	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 175 of the CFTR protein (p.Ile175Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cystic fibrosis (PMID: 7520799, 28546993). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53986). 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 with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR function (PMID: 9305991, 19491324). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000577574	SCV002573972	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, PP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577574	SCV003922694	likely pathogenic	Cystic fibrosis	2025-03-07	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.523A>G (p.Ile175Val) results in a conservative amino acid change located in the transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250706 control chromosomes (gnomAD). c.523A>G has been reported in the literature in the homozygous state in multiple individuals affected with Cystic Fibrosis, including at least one family in which it segregated with the disease phenotype (e.g. Romey_1994, Behar_2017, Alsamri_2020). These data indicate that the variant is very likely to be associated with disease. However, at least 3 publications report experimental evidence evaluating an impact on protein function and showed conflicting evidence of this variant in vitro (e.g. Seibert_1997, Caputo_2009, Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 32662942, 28546993, 38388235, 19491324, 7520799, 9305991). ClinVar contains an entry for this variant (Variation ID: 53986). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003474607	SCV004213498	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-05-29	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000577574	SCV005420800	likely pathogenic	Cystic fibrosis	2024-10-04	criteria provided, single submitter	research	PP1,PM3(strong),PM2,PP3,PP4
Fulgent Genetics, Fulgent Genetics	RCV005031526	SCV005673283	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-06-11	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577574	SCV000679163	not provided	Cystic fibrosis		no assertion provided	literature only