ClinVar Miner

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

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Total submissions: 5
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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.
Integrated Genetics/Laboratory Corporation of America 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

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