Submissions for variant NM_000492.4(CFTR):c.1736A>G (p.Asp579Gly)

dbSNP: rs397508288

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV003227629	SCV003925503	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.
Mendelics	RCV000577633	SCV000886315	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004270	SCV001163146	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV001009377	SCV001169230	pathogenic	Cystic fibrosis; CFTR-related disorder	2015-07-03	criteria provided, single submitter	curation	when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577633	SCV001360490	pathogenic	Cystic fibrosis	2019-11-14	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1736A>G (p.Asp579Gly) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) 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 4e-06 in 250214 control chromosomes (gnomAD). c.1736A>G has been reported in the literature in compound heterozygous state with another pathogenic variant or in homozygous state in multiple individuals affected with Non-classic Cystic Fibrosis (e.g. Al-Atawi_2015, Brancolini_1995, Picci_1998, Salvatore_2004, Sofia_2018). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to cause a considerable decrease in chloride conductance and transport (Sosnay_2013, Van Goor_2014). A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000577633	SCV001579208	pathogenic	Cystic fibrosis	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 579 of the CFTR protein (p.Asp579Gly). This variant is present in population databases (rs397508288, gnomAD no frequency). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 7544319, 15463898, 26494713, 27738188, 27812499). ClinVar contains an entry for this variant (Variation ID: 53365). 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. Experimental studies have shown that this missense change affects CFTR function (PMID: 23891399). 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.
GeneDx	RCV001577799	SCV001805254	pathogenic	not provided	2022-11-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced chloride transport (Sosnay et al., 2013; VanGoor et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); Also known as CFTR c.1868A>G; This variant is associated with the following publications: (PMID: 15463898, 23974870, 25489051, 22658665, 29805046, 16132229, 26823392, 25910067, 26494713, 22423042, 25583415, 23891399, 10094564, 27812499, 31036917, 7544319, 27738188, 31130284)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000577633	SCV002507346	pathogenic	Cystic fibrosis	2019-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000577633	SCV002710204	pathogenic	Cystic fibrosis	2020-07-02	criteria provided, single submitter	clinical testing	The p.D579G pathogenic mutation (also known as c.1736A>G), located in coding exon 13 of the CFTR gene, results from an A to G substitution at nucleotide position 1736. The aspartic acid at codon 579 is replaced by glycine, an amino acid with similar properties. This mutation has been observed in the homozygous state in patients with non-classical cystic fibrosis presentations, including borderline or intermediate sweat chloride levels, mild or no pulmonary disease, and pancreatic sufficiency (Picci L et al. Hum. Mutat. 1999; 13:173; Salvatore D et al. J. Cyst. Fibros. 2004; 3:135-6; Al-Atawi MS et al. BMJ Case Rep, 2015 Oct;2015:). The p.D579G alteration has been reported as a variant of varying clinical consequences (VVCC) and has been identified in trans with a pathogenic mutation in individuals with no disease, CFTR-related disorders, or with cystic fibrosis (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Bombieri C et al. Semin Respir Crit Care Med, 2015 Apr;36:180-93; Terlizzi V et al. J. Med. Genet., 2017 04;54:224-235). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003473465	SCV004213430	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-12-29	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000577633	SCV004809753	pathogenic	Cystic fibrosis	2024-04-04	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577633	SCV000679337	not provided	Cystic fibrosis		no assertion provided	literature only
Natera, Inc.	RCV001831735	SCV002080664	pathogenic	CFTR-related disorder	2017-08-28	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001831735	SCV002507430	pathogenic	CFTR-related disorder	2019-06-18	no assertion criteria provided	clinical testing