Submissions for variant NM_000492.4(CFTR):c.2417A>G (p.Asp806Gly)

gnomAD frequency: 0.00001  dbSNP: rs397508375

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001004476	SCV001163521	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255509	SCV001431942	uncertain significance	not specified	2025-02-03	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2417A>G (p.Asp806Gly) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 179966 control chromosomes. c.2417A>G has been reported in (assumed) compound heterozygous individuals affected with (suspected) cystic fibrosis (Strom_2003, Picci_2010), however, it was also observed in trans with a pathogenic variant (p.F508del) in a newborn with a negative sweat test (Narzi_2007). In addition, the variant was listed to be found in cohorts of CF patients and newborns with positive screening tests, however no second variant was specified in these cases (Atag_2019, Petrova_2020, Bozdogan_2021). These data do not allow clear conclusions about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating that the variant resulted in approximately 50% of normal chloride channel conductance relative to wild type (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 19897426, 12544470, 17594398, 25735457, 25880441, 30548586, 30938940, 33572515, 34405919, 36717774, 38388235). ClinVar contains an entry for this variant (Variation ID: 53487). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001781374	SCV001474365	uncertain significance	not provided	2024-09-25	criteria provided, single submitter	clinical testing	The CFTR c.2417A>G; p.Asp806Gly variant (rs397508375; ClinVar Variation ID: 53487) is reported in the literature in the compound heterozygous state with a second pathogenic variant in individuals affected with cystic fibrosis (Petrova 2019, Strom 2003). It has also been reported with F508del in a newborn with a normal sweat chloride (Narzi 2007). One functional study showed that the variant protein has ~50% of baseline function compared to wild type (Bihler 2024). This variant is only found on two alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.929). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Bihler H et al. In vitro modulator responsiveness of 655 CFTR variants found in people with cystic fibrosis. J Cyst Fibros. 2024 Jul;23(4):664-675. PMID: 38388235. Narzi L et al. Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up. Clin Genet. 2007 Jul;72(1):39-46. Petrova NV et al. Comprehensive genotyping reveals novel CFTR variants in cystic fibrosis patients from the Russian Federation. Clin Genet. 2019 Mar;95(3):444-447. PMID: 30548586. Strom CM et al. Extensive sequencing of the cystic fibrosis transmembrane regulator gene: assay validation and unexpected benefits of developing a comprehensive test. Genet Med. 2003 Jan-Feb;5(1):9-14.
Genome-Nilou Lab	RCV000577591	SCV001822105	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001588875	SCV001822106	likely pathogenic	Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001781374	SCV002022523	likely pathogenic	not provided	2023-02-02	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000577591	SCV002507350	likely pathogenic	Cystic fibrosis	2020-03-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000577591	SCV002732832	uncertain significance	Cystic fibrosis	2023-05-18	criteria provided, single submitter	clinical testing	The p.D806G variant (also known as c.2417A>G), located in coding exon 14 of the CFTR gene, results from an A to G substitution at nucleotide position 2417. The aspartic acid at codon 806 is replaced by glycine, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with cystic fibrosis that also carried p.F508del (Strom CM et al. Genet Med;5:9-14; Petrova NV et al. Clin Genet, 2019 03;95:444-447). This alteration was also reported in trans with the p.F508del mutation in a newborn with a negative sweat test (Narzi L et al. Clin. Genet., 2007 Jul;72:39-46). This alteration has also been identified in an individual diagnosed with pancreatic cancer (Tavano F et al. Mol Med, 2023 Jan;29:14). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577591	SCV003517100	likely pathogenic	Cystic fibrosis	2024-09-09	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 806 of the CFTR protein (p.Asp806Gly). This variant is present in population databases (rs397508375, gnomAD 0.005%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 12544470, 30548586, 32429104). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53487). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001781374	SCV004021564	uncertain significance	not provided	2023-07-10	criteria provided, single submitter	clinical testing	Observed with other CFTR variants, phase (cis or trans) unknown, in individuals with sweat chloride levels or nasal potential difference (NPD) within normal range (Narzi 2007, Tridello 2016); 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; This variant is associated with the following publications: (PMID: 34426522, 30938940, 30548586, 17594398, 12544470, 32429104, 33572515, 25880441, 19897426, 25735457, 27423539, 34996830, 34405919, 36717774)
Baylor Genetics	RCV003473484	SCV004213273	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031497	SCV005673358	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-05-13	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577591	SCV000678997	not provided	Cystic fibrosis		no assertion provided	literature only
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002228157	SCV002507434	likely pathogenic	CFTR-related disorder	2020-03-16	no assertion criteria provided	clinical testing