ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2173G>A (p.Glu725Lys) (rs199791061)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590320 SCV000696888 uncertain significance not provided 2017-03-14 criteria provided, single submitter clinical testing Variant summary: The CFTR c.2173G>A (p.Glu725Lys) involves a conserved nucleotide and results in a replacement of a medium size and acidic Glutamic acid (E) with a large size and basic Lysine (K). 4/5 in silico tools predict the variant to be disease-causing. This variant was found in 11/120750 control chromosomes including broad and large populations of ExAC at a frequency of 0.0000911, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant was reported in patients with CF, Hypertrypsinemia, Primary Sclerosing Cholangitis and suboptimal fertility, however without strong evidence for pathogenicity. It has also been reported in same chromosome (in cis) with c.1766+5G>A - a potentially pathogenic variant (because another nucleotide change c.1766+5G>T is a known pathogenic variant causing splicing defect), arguing against pathogenicity. Due to the lack of stronger clinical evidence and functional studies, the variant is classified as a variant of uncertain significance until more information becomes available.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000590320 SCV000704855 uncertain significance not provided 2016-12-27 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000590320 SCV000883587 uncertain significance not provided 2018-05-23 criteria provided, single submitter clinical testing The CFTR c.2173G>A; p.Glu725Lys variant (rs199791061) has been described in patients with cystic fibrosis, but without strong evidence for pathogenicity (des Georges 2004, Kanavakis 2003). This variant has also been reported in the heterozygous state in one individual with suboptimal fertility and one individual affected with hypertrypsinemia (Gene 2008, Larriba 2005). It is listed as a variant of uncertain significance in ClinVar (Variation ID: 53448), and observed in the general population at an overall frequency of 0.01% (28/277040 alleles) in the Genome Aggregation Database. The glutamic acid at codon 725 is moderately conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is damaging. Due to the lack of functional data regarding this variant, its clinical significance cannot be determined with certainty. References: Des Georges M et al. High heterogeneity of CFTR mutations and unexpected low incidence of cystic fibrosis in the Mediterranean France. J Cyst Fibros. 2004 Dec;3(4):265-72. Gene G et al. N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel. Hum Mutat. 2008 May;29(5):738-49. Kanavakis E et al. Cystic fibrosis in Greece: molecular diagnosis, haplotypes, prenatal diagnosis and carrier identification amongst high-risk individuals. Clin Genet. 2003 May;63(5):400-9. Larriba S et al. Molecular evaluation of CFTR sequence variants in male infertility of testicular origin. Int J Androl. 2005 Oct;28(5):284-90.
CFTR-France RCV001009489 SCV001169584 pathogenic CFTR-related disorders 2018-03-26 criteria provided, single submitter curation
Ambry Genetics RCV001014674 SCV001175411 uncertain significance Inborn genetic diseases 2020-03-26 criteria provided, single submitter clinical testing The p.E725K variant (also known as c.2173G>A), located in coding exon 14 of the CFTR gene, results from a G to A substitution at nucleotide position 2173. The glutamic acid at codon 725 is replaced by lysine, an amino acid with similar properties. This variant was identified in cis with an intronic alteration on one allele in a cohort of individuals with cystic fibrosis (des Georges M et al. J. Cyst. Fibros., 2004 Dec;3:265-72). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV001009489 SCV001325751 uncertain significance CFTR-related disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV000577536 SCV001495828 uncertain significance Cystic fibrosis 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 725 of the CFTR protein (p.Glu725Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs199791061, ExAC 0.02%). This variant has been observed in individual(s) with cystic fibrosis (PMID: 15698946, 18306312, 12752573). ClinVar contains an entry for this variant (Variation ID: 53448). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000590320 SCV001501416 pathogenic not provided 2020-12-01 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000577536 SCV001822096 likely pathogenic Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577536 SCV000678980 not provided Cystic fibrosis no assertion provided literature only

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