Submissions for variant NM_000492.4(CFTR):c.1580A>G (p.Glu527Gly)

gnomAD frequency: 0.00002  dbSNP: rs374453187

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000667996	SCV000792534	uncertain significance	Cystic fibrosis	2017-06-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004461	SCV001163506	likely pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000667996	SCV001822062	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000667996	SCV002703389	uncertain significance	Cystic fibrosis	2024-03-29	criteria provided, single submitter	clinical testing	The p.E527G variant (also known as c.1580A>G), located in coding exon 11 of the CFTR gene, results from an A to G substitution at nucleotide position 1580. The glutamic acid at codon 527 is replaced by glycine, an amino acid with similar properties. This variant was reported in a compound heterozygous state with p.F508del in a newborn with elevated immunoreactive trypsinogen, and a normal sweat chloride concentration (Castellani C et al. Am. J. Hum. Genet. 1999 Jan; 64(1):303-4; Castellani C et al. J. Med. Genet. 2001 Mar; 38(3):202-5). This variant has been reported in combination with a different CF-causing mutation in an infant with a normal sweat chloride concentration (Ooi CY et al. Pediatrics, 2015 Jun;135:e1377-85). This amino acid position is well 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	RCV000667996	SCV003021036	uncertain significance	Cystic fibrosis	2022-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 527 of the CFTR protein (p.Glu527Gly). This variant is present in population databases (rs374453187, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of CFTR-related conditions (PMID: 9915972, 25963003). ClinVar contains an entry for this variant (Variation ID: 552690). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003117470	SCV003800789	uncertain significance	not specified	2024-08-01	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1580A>G (p.Glu527Gly) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) 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 2.4e-05 in 250728 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1580A>G has been reported in the literature in at least two compound heterozygous individuals who were identified during newborn screening (Castellani_1999, Ooi_2015). Both individuals had elevated immunoreactive trypsinogen during newborn screening and a known pathogenic variant on the second allele, but neither individuals had elevated sweat chloride levels during follow-up. Therefore, these reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At least one publication reports experimental evidence that this variant results in 77% chloride conductance compared to wildtype in vitro (e.g. Bihler_2023). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 9915972, 25963003, 19897426). ClinVar contains an entry for this variant (Variation ID: 552690). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003472092	SCV004213326	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-07	criteria provided, single submitter	clinical testing