ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.489+1G>T (rs78756941)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
American College of Medical Genetics and Genomics (ACMG) RCV000043565 SCV000071409 pathogenic Cystic fibrosis 2004-03-03 practice guideline curation Converted during submission to Pathogenic.
CFTR2 RCV000043565 SCV000071461 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Invitae RCV000043565 SCV000075172 pathogenic Cystic fibrosis 2018-12-12 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the CFTR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs78756941, ExAC 0.01%). This splicing variant is clearly defined as a cystic fibrosis (CF) causative allele (PMID: 23974870) and is included in the American College of Medical Genetics (ACMG) panel of CF variants (PMID: 15371902). This variant is also known as 621+1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 38799). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). For these reasons, this variant has been classified as Pathogenic.
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000043565 SCV000236526 pathogenic Cystic fibrosis 2014-10-15 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000657900 SCV000331547 pathogenic not provided 2015-07-16 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000043565 SCV000584077 pathogenic Cystic fibrosis 2016-05-12 criteria provided, single submitter research
GeneDx RCV000657900 SCV000779664 pathogenic not provided 2018-05-07 criteria provided, single submitter clinical testing The c.489+1G>T (also reported as 621+1G>T) splice site variant is a well-described pathogenic variant reported in association with cystic fibrosis and other CFTR-related disorders (for examples see Zielenski et al., 1991; Amato et al., 2012, Wilschanski et al., 2006). This pathogenic variant destroys the canonical splice donor site in intron 4 results in abnormal gene splicing (Castellani et al., 2008). We interpret c.489+1G>T as a pathogenic variant.
Mendelics RCV000043565 SCV000886212 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763152 SCV000893739 pathogenic Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2018-10-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001001802 SCV001159464 pathogenic not specified 2018-07-19 criteria provided, single submitter clinical testing The CFTR c.489+1G>T variant (rs78756941), also known as 621+1G>T, has been reported in patients diagnosed with the pancreatic insufficient form of cystic fibrosis (Zielenski 1991, Sheridan 2011, Ooi 2012, Sosnay 2013). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 38799) and is seen in the general population at a low overall frequency of 0.008% (20/240558 alleles) in the Genome Aggregation Database. Computational algorithms (Alamut v.2.11) predict the loss of the canonical splice donor, leading to the production of aberrant RNA transcripts (Sheridan 2011). Based on the above information, this variant is classified as severely pathogenic. References: Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012; 11(5):355-62. Sheridan M et al. CFTR transcription defects in pancreatic sufficient cystic fibrosis patients with only one mutation in the coding region of CFTR. J Med Genet. 2011; 48(4):235-41. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. Zielenski J et al. Identification of mutations in exons 1 through 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics. 1991 May;10(1):229-35.
Baylor Genetics RCV001004431 SCV001163476 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
Counsyl RCV000043565 SCV000485154 pathogenic Cystic fibrosis 2015-11-27 no assertion criteria provided clinical testing

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