Submissions for variant NM_000492.4(CFTR):c.1438G>A (p.Gly480Ser)

dbSNP: rs79282516

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000577421	SCV000797069	uncertain significance	Cystic fibrosis	2018-01-12	criteria provided, single submitter	clinical testing
Invitae	RCV000577421	SCV001516715	uncertain significance	Cystic fibrosis	2022-06-08	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 480 of the CFTR protein (p.Gly480Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 20059485, 24958810, 26708955, 26730394). ClinVar contains an entry for this variant (Variation ID: 53254). 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. This variant disrupts the p.Gly480 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1376016, 7757078, 9150159, 26708955). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
GeneDx	RCV001753465	SCV001986038	uncertain significance	not provided	2021-02-25	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Co-observed with a second CFTR variant, phase unknown, in an individual with cystic fibrosis (Cao 2015) and observed in an individual with congenital absence of the vas deferens (Sharma 2014); This variant is associated with the following publications: (PMID: 24958810, 29261177, 26730394)
Genome-Nilou Lab	RCV000577421	SCV002027405	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000577421	SCV002507368	uncertain significance	Cystic fibrosis	2020-03-18	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000577421	SCV002573940	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: PM2_SUP, PM3, PM5_STR, PP3, PP4
Ambry Genetics	RCV000577421	SCV002696264	uncertain significance	Cystic fibrosis	2017-08-04	criteria provided, single submitter	clinical testing	The p.G480S variant (also known as c.1438G>A), located in coding exon 11 of the CFTR gene, results from a G to A substitution at nucleotide position 1438. The glycine at codon 480 is replaced by serine, an amino acid with similar properties. This variant was identified in one individual with congenital absence of the vas deferens (CAVD); another CFTR alteration was not identified (Sharma H, et al. Mol. Hum. Reprod. 2014 Sep; 20(9):827-35). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this variant remains unclear.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577421	SCV000679325	not provided	Cystic fibrosis		no assertion provided	literature only
Natera, Inc.	RCV001826611	SCV002080597	uncertain significance	CFTR-related disorder	2019-02-15	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001826611	SCV002507452	uncertain significance	CFTR-related disorder	2020-03-18	no assertion criteria provided	clinical testing