ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2981T>G (p.Phe994Cys) (rs397508469)

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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 RCV000855590 SCV000696940 uncertain significance not specified 2019-03-29 criteria provided, single submitter clinical testing Variant summary: CFTR c.2981T>G (p.Phe994Cys) results in a non-conservative amino acid change located in the transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245896 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant of interest has been reported in the literature and in multiple databases in a male patient affected with Congenital Bilateral Absence of the Vas Deferens (CBAVD) who carried a severe disease variant (likely deltaF508) on the other allele (Dorfman 2010, Claustres 2017); however this patient also carried a mild pathogenic variant (TG12T5) in cis, which could explain his phenotype. These reports therefore do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000586753 SCV000862907 uncertain significance not provided 2018-08-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000855590 SCV001158155 uncertain significance not specified 2019-01-28 criteria provided, single submitter clinical testing The CFTR c.2981T>G; p.Phe994Cys variant (rs397508469) is reported in an individual with congenital bilateral absence of the vas deferens (CBAVD) who also carries 5T on the same allele and F508del on the other allele (see database link). This variant is reported as uncertain in ClinVar (Variation ID: 53612). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The phenylalanine at codon 994 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. REFERENCES Link to SickKids database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=797
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577330 SCV000679421 not provided Cystic fibrosis no assertion provided literature only

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