ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.330C>A (p.Asp110Glu) (rs397508537)

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Total submissions: 7
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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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000577359 SCV000696964 pathogenic Cystic fibrosis 2020-08-17 criteria provided, single submitter clinical testing Variant summary: CFTR c.330C>A (p.Asp110Glu) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251104 control chromosomes (gnomAD). c.330C>A has been reported in the literature in multiple individuals affected with varying phenotypes, predominantly presenting as a mild phenotype, which patients have a borderline sweat chloride level, pancreatic sufficiency, and normal lung function (Colombo_2006, Padoan_2002, Sermet-Gaudelus__2010, Tzetis_2001, Xie_2015, McCague_2019). These data indicate that the variant is very likely to be associated with disease. However, functional studies have indicated that the variant greater affects chloride transport (van Goor_2013, Raraigh_2018) 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. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and pathogenic (2x). Based on the evidence outlined above, the variant was 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
CFTR-France RCV001009539 SCV001169634 pathogenic Cystic fibrosis; CFTR-related disorders 2018-03-09 criteria provided, single submitter curation the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both
Invitae RCV000577359 SCV001589606 pathogenic Cystic fibrosis 2020-04-01 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 110 of the CFTR protein (p.Asp110Glu). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous in and in combination with another CFTR variant in several individuals affected with cystic fibrosis (PMID: 11883825, 10790222). ClinVar contains an entry for this variant (Variation ID: 53714). This variant has been reported to affect CFTR protein function (PMID: 29805046, 23891399). This variant disrupts the p.Asp110 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9272157, 18373402, 19897426, 22724884). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577359 SCV000679435 not provided Cystic fibrosis no assertion provided literature only

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