ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577536 SCV000678980 not provided Cystic fibrosis no assertion provided literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000590320 SCV000704855 uncertain significance not provided 2016-12-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.

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