Submissions for variant NM_000492.4(CFTR):c.1841A>G (p.Asp614Gly)

gnomAD frequency: 0.00003  dbSNP: rs201124247

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577786	SCV000696877	pathogenic	Cystic fibrosis	2022-04-18	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1841A>G (p.Asp614Gly) results in a non-conservative amino acid change located in the ABC transporter-like (IPR003439) and AAA+ ATPase domains (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 3.1e-05 in 229320 control chromosomes. c.1841A>G has been reported in compound heterozygosity with another pathogenic variant in multiple individuals affected with CF and CBAVD in the literature (e.g. Wilschanski_1995, Grangeia_2004, Lucarelli_2015, Pereira_2019, McCague_2019). Many of these patients have been reported with borderline sweat chloride levels and/or as pancreatic-sufficient, suggesting that the variant may be associated with a milder non-classical CF phenotype. The variant was also detected in compound heterozygosity with the common severe disease causing variant CFTR p.Phe508del in three siblings diagnosed in adulthood with atypical CF phenotypes of varying degrees of severity, leading the authors to conclude that this variant may be a "mild" CF mutation (e.g. Castaldo_2006). Collectively, these data indicate that the variant is likely to be associated with disease. Several publications report in-vitro experimental evidence evaluating an impact on protein function, reporting that the variant reduced CFTR processing in multiple cell lines (e.g. Pasyk_1998 Vankeerberghen_1998, Sosnay_2013). The variant was also observed to at least partially reduce measured current activity and alter the dynamics of channel gate opening and closing (Pasyk_1998, Sosnay_2013). Four clinical diagnostic laboratories and the CFTR-France database have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as Pathogenic/Likely pathogenic (n=4). The CFTR2 database reports the variant as having varying consequences as some individuals with this variant and another pathogenic variant have CF, while others do not, indicating that clinical criteria alone should be used in the diagnosis of patients with this variant. Based on the evidence outlined above, the variant was classified as pathogenic for non-classic CF.
Mendelics	RCV000577786	SCV000886353	pathogenic	Cystic fibrosis	2023-03-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004275	SCV001163151	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV001009371	SCV001169224	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
Invitae	RCV000577786	SCV001578414	pathogenic	Cystic fibrosis	2023-09-24	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 614 of the CFTR protein (p.Asp614Gly). This variant is present in population databases (rs201124247, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital absence of vas deferens and/or cystic fibrosis (PMID: 12454843, 16478680, 17413420, 21679131). ClinVar contains an entry for this variant (Variation ID: 53403). 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: 9736778). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000577786	SCV001822089	likely pathogenic	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV002227057	SCV002506290	pathogenic	not provided	2023-10-02	criteria provided, single submitter	clinical testing	The CFTR c.1841A>G; p.Asp614Gly variant (rs201124247) is reported in the literature in the compound heterozygous state with another pathogenic CFTR variant individuals with phenotypes ranging from cystic fibrosis with or without pancreatic insufficiency to congenital absence of the vas deferens only (Castaldo 2006, Durno 2002, Grangeia 2007, Lucarelli 2015, McCague 2019, Pereira 2019, Tomaiuolo 2011, Wilschanski 1995). This variant is also reported in ClinVar (Variation ID: 53403), but is only observed on seven alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The aspartate at codon 614 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.942). In vitro functional analyses demonstrate aberrant protein processing leading to partial channel function (Pasyk 1998, Sosnay 2013, Vankeerberghen 1998). Based on available information and the range of phenotypes observed, this variant is considered to be pathogenic with varying clinical consequences. References: Castaldo G et al. Phenotypic discordance in three siblings affected by atypical cystic fibrosis with the F508del/D614G genotype. J Cyst Fibros. 2006 Aug;5(3):193-5. PMID: 16478680. Durno C et al. Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis. Gastroenterology. 2002 Dec;123(6):1857-64. PMID: 12454843. Grangeia A et al. Molecular characterization of the cystic fibrosis transmembrane conductance regulator gene in congenital absence of the vas deferens. Genet Med. 2007 Mar;9(3):163-72. PMID: 17413420. Lucarelli M et al. A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis. Mol Med. 2015 Apr 21;21(1):257-75. PMID: 25910067. McCague AF et al. Correlating Cystic Fibrosis Transmembrane Conductance Regulator Function with Clinical Features to Inform Precision Treatment of Cystic Fibrosis. Am J Respir Crit Care Med. 2019 May 1;199(9):1116-1126. PMID: 30888834. Pasyk EA et al. A conserved region of the R domain of cystic fibrosis transmembrane conductance regulator is important in processing and function. J Biol Chem. 1998 Nov 27;273(48):31759-64. PMID: 9822639. Pereira SV et al. Novel, rare and common pathogenic variants in the CFTR gene screened by high-throughput sequencing technology and predicted by in silico tools. Sci Rep. 2019 Apr 17;9(1):6234. PMID: 30996306. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. PMID: 23974870. Tomaiuolo R et al. Enhanced frequency of CFTR gene variants in couples who are candidates for assisted reproductive technology treatment. Clin Chem Lab Med. 2011 Aug;49(8):1289-1293. PMID: 21679131. Vankeerberghen A et al. Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. Hum Mol Genet. 1998 Oct;7(11):1761-9. PMID: 9736778. Wilschanski M et al. Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations. J Pediatr. 1995 Nov;127(5):705-10. PMID: 7472820.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000577786	SCV002507383	pathogenic	Cystic fibrosis	2022-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000577786	SCV002712630	pathogenic	Cystic fibrosis	2023-10-11	criteria provided, single submitter	clinical testing	The p.D614G pathogenic mutation (also known as c.1841A>G), located in coding exon 14 of the CFTR gene, results from an A to G substitution at nucleotide position 1841. The aspartic acid at codon 614 is replaced by glycine, an amino acid with similar properties. This mutation has been detected in three individuals from one family with mild CF who also carried the p.F508del pathogenic mutation in trans (Castaldo G et al. J. Cyst. Fibros., 2006 Aug;5:193-5). This alteration has also been detected in individuals with CFTR-related disorders, including CBAVD and pancreatitis (Zielenski J et al. Am. J. Hum. Genet., 1995 Oct;57:958-60; Gomez-Lira M et al. Eur. J. Hum. Genet., 2003 Jul;11:543-6; Amato F et al. J Mol Diagn, 2012 Jan;14:81-9). The p.D614G alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Nat. Genet. 2013 Oct; 45(10):1160-7; Sosnay PR et al. Pediatr. Clin. North Am. 2016 Aug;63(4):585-98). In addition, in vitro functional studies have demonstrated this alteration results in decreased chlorine channel activity and abnormal protein processing (Pasyk EA et al. J. Biol. Chem., 1998 Nov;273:31759-64; Vankeerberghen A et al. Hum. Mol. Genet., 1998 Oct;7:1761-9; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). 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 the supporting evidence, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV001831738	SCV004116144	likely pathogenic	CFTR-related disorder	2022-10-12	criteria provided, single submitter	clinical testing	The CFTR c.1841A>G variant is predicted to result in the amino acid substitution p.Asp614Gly. This variant has been reported in individuals with an indeterminate cystic fibrosis phenotype (Supplementary Table 2, Sosnay et al. 2013. PubMed ID: 23974870; Masica et al. 2014. PubMed ID: 25489051) and in an individual with congenital bilateral absence of the vas deferens (CBAVD, Amato et al. 2011. PubMed ID: 22020151). This variant was also reported in the compound heterozygous state with the F508del variant in three siblings with late-diagnosed mild cystic fibrosis, however one sibling had severe symptoms while the other two had a milder disease course (Castaldo et al. 2006. PubMed ID: 16478680). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117232062-A-G). Taken together, this variant is interpreted as likely pathogenic.
Baylor Genetics	RCV003473469	SCV004211620	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-02-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002227057	SCV004221668	pathogenic	not provided	2022-10-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00014 (4/28740 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in patients with classical or atypical cystic fibrosis (CF) (PMIDs: 33424627 (2020), 30996306 (2019), 25910067 (2015), 16801189 (2006), 16478680 (2006), 12454843 (2002)), congenital bilateral absence of vas deferens (CBAVD) (PMIDs: 25910067 (2015), 15333598 (2004)), pancreatic insufficiency (PMIDs: 30888834 (2019), 16478680 (2006)), and is often reported in trans with another pathogenic CFTR variant in affected individuals. Functional studies have indicated that this variant causes abnormal protein folding, abnormal rates of cell maturation, and altered rates of channel opening (PMIDs: 9736778 (1998), 9822639 (1998), 29040544 (2017), 30297908 (2018), 33468668 (2021), 35418593 (2022)). 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.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577786	SCV000679343	not provided	Cystic fibrosis		no assertion provided	literature only
Natera, Inc.	RCV001831738	SCV002080681	pathogenic	CFTR-related disorder	2017-08-28	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001831738	SCV002507467	pathogenic	CFTR-related disorder	2022-01-31	no assertion criteria provided	clinical testing