ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2421A>G (p.Ile807Met) (rs144055758)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000725433 SCV000883597 uncertain significance not provided 2017-06-18 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725433 SCV000336902 uncertain significance not provided 2017-11-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515401 SCV000611383 uncertain significance Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral absence of the vas deferens 2017-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000313144 SCV000696899 likely benign not specified 2016-11-01 criteria provided, single submitter clinical testing Variant summary: This missense variant involves the alteration of a non-conserved nucleotide and 4/5 in silico tools predict a pathogenic outcome. However, the functional study showed this variant did not affect maturation and caused no significant alterations in the intrinsic chloride channel activity (Vankeerberghen_1998). The variant was observed in controls including the large and broad cohorts of the ExAC project at an allele frequency of 0.073% (83/113596 chr) with 1 homozygote occurrence. This frequency does not exceed the maximal expected allele frequency of 0.63% for a pathogenic CFTR variant for chronic pancreatitis risk; despite this, the variant may still represents as a rare polymorphism. This variant has been detected in ICP pts and healthy controls with comparable allele frequencies (LaRusch_2014). Multiple ICP pts reported with this variant of interest also carried another disease variant in either CFTR or the known CPANC causative gene SPINK1 (Masson_2013, Pelletier _2010, and Schneider_2011), indicating the contribution of this particular variant to pancreatitis is relatively low. In addition, multiple studies list this variant as neutral variant with no clinical consequence. (Fanen_2014, Castellani_2008). Multiple clinical labs list this variant with classification of VUS, without evidence to independently review. Considering all, this variant is classified as a probably benign variant until additional information becomes available.
Invitae RCV000197986 SCV000254590 benign Cystic fibrosis 2018-01-08 criteria provided, single submitter clinical testing
Johns Hopkins Genomics,Johns Hopkins University RCV000197986 SCV000992327 likely pathogenic Cystic fibrosis 2019-02-03 criteria provided, single submitter clinical testing Previously reported CFTR variant. There are several additional literature reports (individual case reports) often associated with milder phenotypes. This variant (rs144055758) is rare (<0.1% minor allele frequency) in large population databases. Two bioinformatic tools queried predict that this substitution would not be tolerated, and the tyrosine residue is completely evolutionarily conserved across assessed species. Functional assessment of this variant soon to be published by the CFTR2 Project ( shows a reduction in chloride conductance to approximately 20% of wild type, which is consistent with the varying phenotypes observed. This variant is likely pathogenic, associated with varying clinical consequences.

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