Submissions for variant NM_000492.4(CFTR):c.1645A>C (p.Ser549Arg)

dbSNP: rs121908757

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000043664	SCV000071529	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
PharmGKB	RCV000211346	SCV000268175	drug response	ivacaftor response - Efficacy	2021-03-24	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781222	SCV000919126	pathogenic	not specified	2018-01-26	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.1645A>C (p.Ser549Arg) variant located in the ABC transporter-like domain involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/245714 control chromosomes (gnomAD and publication controls) at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The missense variant, Ser549Arg is caused by multiple nucleotide changes, c.1645A>C, c.1647T>G, and c.1647T>A. The missense change, Ser549Arg, has been reported in multiple affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics	RCV001004464	SCV001163509	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000043664	SCV001169404	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043664	SCV001587478	pathogenic	Cystic fibrosis	2022-10-27	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with cystic fibrosis or congenital absence of the vas deferens (PMID: 10923036, 11005149, 16840743, 23082198). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121908757, gnomAD 0.0009%). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 549 of the CFTR protein (p.Ser549Arg). ClinVar contains an entry for this variant (Variation ID: 38733). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser549 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1695717, 1721624, 7544319, 22658665, 23974870, 24440181, 25042876, 29360847). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Mendelics	RCV002247407	SCV002518675	pathogenic	Hereditary pancreatitis	2022-05-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003466883	SCV004215793	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2021-12-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003476914	SCV004221665	pathogenic	not provided	2022-10-21	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/250924 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with cystic fibrosis (CF) (PMID: 1903761 (1991)), pancreatic cancer (PMID: 19885835 (2010)), and congenital bilateral absence of vas deferens (CBAVD) (PMID: 10923036 (2000)). This variant is often detected in trans with another pathogenic CFTR variant in affected individuals (PMIDs: 2236053 (1990), 10652351 (2000)). Functional studies have demonstrated that this variant demonstrates defective chloride transport ability and defective channel gating (PMID: 22293084 (2012)). Other variants at the same residue are known to be pathogenic (PMIDs: 2236053 (1990), 10204861 (1999), 10652351 (2000)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
OMIM	RCV000043664	SCV000071686	pathogenic	Cystic fibrosis	2000-02-04	no assertion criteria provided	literature only
Counsyl	RCV000043664	SCV000485151	pathogenic	Cystic fibrosis	2016-02-03	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826533	SCV002080629	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing