ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.335A>G (p.Asp112Gly) (rs770241677)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000704 SCV001157745 uncertain significance not specified 2018-07-11 criteria provided, single submitter clinical testing The CFTR c.335A>G; p.Asp112Gly variant (rs770241677) is reported in the literature in one individual with CFTR-related metabolic syndrome in trans to a CFTR pathogenic frameshift variant (Prach 2013). The p.Asp112Gly variant is found in the Latino population with an overall allele frequency of 0.012% (4/33454 alleles) in the Genome Aggregation Database. The aspartate at codon 112 is moderately conserved and occurs in CFTR extracellular loop 1, a region affected in some cystic fibrosis patients (see link to CFTR2 database) and implicated in regulating CFTR pore gating (Cui 2014, Infield 2016). However, computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated and electrophysiology studies of Xenopus oocytes expressing variant CFTR constructs suggested that another variant in the same codon, p.Asp112Arg, had similar conductance properties to the wildtype protein (Cui 2014). Additional computational analyses (Alamut v.2.11) predict that the c.335A>G; p.Asp112Gly variant may impact splicing by creating a novel cryptic donor splice site, however, this finding would require studies of the CFTR mRNA to confirm. Due to limited information, the clinical significance of the p.Asp112Gly variant is uncertain at this time. References: CFTR2 database: https://cftr2.org/ Cui G et al. Three charged amino acids in extracellular loop 1 are involved in maintaining the outer pore architecture of CFTR. J Gen Physiol. 2014 Aug;144(2):159-79. Infield DT et al. Positioning of extracellular loop 1 affects pore gating of the cystic fibrosis transmembrane conductance regulator. Am J Physiol Lung Cell Mol Physiol. 2016 Mar 1;310(5):L403-14. Prach L et al. Novel CFTR variants identified during the first 3 years of cystic fibrosis newborn screening in California. J Mol Diagn. 2013 Sep;15(5):710-22.
Invitae RCV001246603 SCV001419968 uncertain significance Cystic fibrosis 2019-03-29 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 112 of the CFTR protein (p.Asp112Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs770241677, ExAC 0.009%). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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