ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1A>G (p.Met1Val) (rs397508328)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000056356 SCV000071512 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Counsyl RCV000056356 SCV000220541 likely pathogenic Cystic fibrosis 2014-07-23 criteria provided, single submitter literature only
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755921 SCV000883590 pathogenic not provided 2018-06-11 criteria provided, single submitter clinical testing The CFTR c.1A>G; p.Met1? variant (rs397508328) has been described in several individuals diagnosed with cystic fibrosis, and often associated with pancreatic insufficiency (see link to CFTR2 database). It is reported as pathogenic in ClinVar (Variation ID: 53423) and observed in the European (Non-Finnish) population at a low overall frequency of 0.004% (5/111584 alleles) in the Genome Aggregation Database. This variant affects the translation initiation codon of the CFTR gene and in vitro functional studies of this variant demonstrate severe defects in CFTR maturation and chloride transport (<1% of wildtype) (Van Goor 2014). In addition, other variants that affect the start codon in exon 1 (c.2T>C, c.2T>A, c.3G>T) have been described in individuals with pancreatic insufficient cystic fibrosis and are considered pathogenic (Bienvenu 2005, Claustres 1993, Hughes 1996). Based on available information, this variant is considered pathogenic. References: CFTR2 database: Bienvenu T et al. Spectrum of CFTR mutations on Réunion Island: impact on neonatal screening. Hum Biol. 2005 Oct;77(5):705-14. Claustres M et al. Analysis of the 27 exons and flanking regions of the cystic fibrosis gene: 40 different mutations account for 91.2% of the mutant alleles in southern France. Hum Mol Genet. 1993 Aug;2(8):1209-13. Hughes D et al. Mutation characterization of CFTR gene in 206 Northern Irish CF families: thirty mutations, including two novel, account for approximately 94% of CF chromosomes. Hum Mutat. 1996;8(4):340-7. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 Jan;13(1):29-36.
Mendelics RCV000056356 SCV000886318 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
CFTR-France RCV000056356 SCV001169419 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000056356 SCV001437252 pathogenic Cystic fibrosis 2020-09-21 criteria provided, single submitter clinical testing Variant summary: CFTR c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251892 control chromosomes (gnomAD). c.1A>G has been reported in the literature in multiple individuals affected with Classic Cystic Fibrosis (Cheadle_1993, Cheadle_1994, desGeorges_2004, Gelfi_1996, Dugueperoux_2005, McCague_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and results in severe defects in CFTR mRNA expression, CFTR maturation and chloride transport (VanGoor_2014). Four ClinVar submitters, including one expert panel (CFTR2), (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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