ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.221G>A (p.Arg74Gln) (rs142540482)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000177074 SCV000602983 uncertain significance not specified 2016-12-03 criteria provided, single submitter clinical testing
Counsyl RCV000046556 SCV000794964 uncertain significance Cystic fibrosis 2017-10-24 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000589418 SCV000228894 uncertain significance not provided 2017-07-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589418 SCV000696890 uncertain significance not provided 2016-12-07 criteria provided, single submitter clinical testing Variant summary: The CFTR c.221G>A (p.Arg74Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. This variant was found in 23/127148 control chromosomes at a frequency of 0.0001809, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). Multiple publications cite the variant in individuals with pancreatitis, without strong evidence for causality. In several patients, the variant was reported along with R297Q (VUS - possibly benign by LCA), but it is unclear if the variants are in cis or trans. Additionally, the variant was found to be associated with pancreatitis when patients also have SPINK1 pathogenic N34S, but not alone (LaRusch_2014). One cinical diagnostic laboratory/reputable database has classified this variant as a VUS. Taken together, until additional evidence becomes available, this variant is classified as VUS.
Invitae RCV000046556 SCV000074569 uncertain significance Cystic fibrosis 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 74 of the CFTR protein (p.Arg74Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs142540482, ExAC 0.03%). This variant has been reported in several individuals affected with chronic pancreatitis (PMID: 25033378, 17003641, 22427236, 21520337), but has not been reported in individuals with cystic fibrosis. ClinVar contains an entry for this variant (Variation ID: 53456) Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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