ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.330C>A (p.Asp110Glu) (rs397508537)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV000660830 SCV000783069 drug response ivacaftor response - Efficacy 2018-03-22 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
Integrated Genetics/Laboratory Corporation of America RCV000577359 SCV000696964 pathogenic Cystic fibrosis 2017-07-17 criteria provided, single submitter clinical testing Variant summary: The CFTR c.330C>A (p.Asp110Glu) variant located in the first extracellular loop (ECL1 via Cui_2014) involves the alteration of a non-conserved nucleotide and 3/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 120396 control chromosomes. Multiple publications cite the variant in affected individuals with varying phenotypes, predominantly presenting as a mild phenotype, which patients have a borderline sweat chloride level, pancreatic sufficiency, and normal lung function. However, functional studies have indicated that the variant greater affects chloride transport (van Goor_2013) and significantly longer mean burst durations (Cui_2014 and Infield_2016). Authors further go on to state "the structure of ECL1 must be tuned delicately to maintain function...none of the charge-retaining mutations identified in ECL1 are able to completely rescue the mutant channel behavior to that of WT-CFTR. This is likely the result of a requirement for very specific bond angles within a network of charged residues that control the architecture of ECL1"(Cui_2014)." Furthermore, another variant at this location D110H has been classified as "pathogenic" by LCA, along with another variant being reported D110R (Cui_2014), therefore, suggesting this location is a mutational hotspot and important for protein function. The variant of interest has been reported by multiple databases but without a clear classification being provided. Therefore, due to the functional impact of the variant via studies, located in a function domain and mutational hotspot, the variant of interest has been classified as "pathogenic."
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000596840 SCV000708644 pathogenic not provided 2017-05-23 criteria provided, single submitter clinical testing
Counsyl RCV000577359 SCV000796470 uncertain significance Cystic fibrosis 2017-12-14 criteria provided, single submitter clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577359 SCV000679435 not provided Cystic fibrosis no assertion provided literature only

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