ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.4046G>A (p.Gly1349Asp) (rs193922525)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000029536 SCV000245910 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
PharmGKB RCV000211255 SCV000268237 drug response ivacaftor response - Efficacy 2018-03-23 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 RCV000029536 SCV000052188 pathogenic Cystic fibrosis 2019-09-17 criteria provided, single submitter clinical testing Variant summary: CFTR c.4046G>A (p.Gly1349Asp) results in a non-conservative amino acid change located in the AAA+ ATPase (IPR003593) and ABC transporter-like (IPR003439) domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251176 control chromosomes (gnomAD). c.4046G>A has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Brancolini_1995, Castaldo_2005, Petrova_2019). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated a significant impact of the variant on protein function including, substantial destabilization of the active state of CFTR and aberrant CFTR-dependent HCO-3 transport (Wilkinson_1996, Choi_2001). Two ClinVar submitters, including the reputable CFTR2 database, (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000029536 SCV000486940 likely pathogenic Cystic fibrosis 2016-09-08 criteria provided, single submitter clinical testing
CFTR-France RCV000029536 SCV001169383 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Invitae RCV000029536 SCV001588886 pathogenic Cystic fibrosis 2019-05-04 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 1349 of the CFTR protein (p.Gly1349Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another CFTR variant in individuals affected with cystic fibrosis (PMID: 26911355, 7544319, 10200050, 23974870, Invitae). ClinVar contains an entry for this variant (Variation ID: 35881). This variant has been reported to affect CFTR protein function (PMID:17353351, 25489051, 23620589). For these reasons, this variant has been classified as Pathogenic.

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