ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.40A>G (p.Lys14Glu) (rs397508673)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000586965 SCV000697006 uncertain significance not provided 2016-06-29 criteria provided, single submitter clinical testing Variant summary: The CFTR c.40A>G (p.Lys14Glu) variant causes a missense change involving a conserved nucleotide, resulting in a replacement of a large, basic amino acid, Lysine (K) with a medium, acidic amino acid, Glutamic acid (E) located outside of a known functional domain. 2/4 in silico tools (MutationTaster not captured here due to low p-value) predict a benign outcome for this substitution. This variant is absent in 120934 control chromosomes. It has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant has been classified as a variant of uncertain significance (VUS), until additional information becomes available.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000586965 SCV000859015 uncertain significance not provided 2017-12-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002549 SCV001160519 uncertain significance not specified 2019-04-24 criteria provided, single submitter clinical testing The CFTR c.40A>G; p.Lys14Glu variant, to our knowledge, is not reported in the medical literature but is reported as uncertain significance in ClinVar (Variation ID: 495943). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The lysine at codon 14 is moderately conserved, and computational analyses (SIFT: damaging; PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Lys14Glu variant is uncertain at this time.
Johns Hopkins Genomics,Johns Hopkins University RCV001200894 SCV001371814 uncertain significance Cystic fibrosis 2020-01-29 criteria provided, single submitter clinical testing CFTR c.40A>G has not been reported in patients with cystic fibrosis to our knowledge. Two ClinVar submitters classify this substitution as a variant of uncertain clincal significance. This CFTR variant (rs397508673) is rare (<0.1%) in a large population dataset (gnomAD: 1/250876 total alleles; 0.0004%; no homozygotes). Of three bioinformatics tools queried, two predict that p.Lys14Glu would be tolerated, while a third predicts that it would be damaging. The lysine residue at this position is conserved in most mammalian species assessed. We consider the clinical significance of c.40A>G to be uncertain at this time.

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