ClinVar Miner

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

dbSNP: rs397508288
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Total submissions: 14
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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 2023-08-12 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

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