ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.638G>A (p.Gly213Glu) (rs775701644)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000765923 SCV000897343 uncertain significance Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral absence of the vas deferens 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780120 SCV000917164 uncertain significance not specified 2018-09-11 criteria provided, single submitter clinical testing Variant summary: CFTR c.638G>A (p.Gly213Glu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 277164 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.638G>A has been reported in the literature in individuals affected with Cystic Fibrosis without strong evidence for or against causality, thus these reports do not provide unequivocal conclusions about association of the variant with Chronic Pancreatitis Risk(Seia_2009, Lucarelli_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000469964 SCV000552131 uncertain significance Cystic fibrosis 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 213 of the CFTR protein (p.Gly213Glu). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs775701644, ExAC 0.001%). This variant has been reported in a compound heterozygous state with a pathogenic variant p.Arg352Gln in a neonate with a positive newborn screening result based on immunoreactive trypsinogen assay.  However, sweat test results were within normal range, suggesting that this variant is not deleterious (PMID: 19318035). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; 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.

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