ClinVar Miner

Submissions for variant NM_198253.3(TERT):c.3399A>G (p.Ter1133Trp)

dbSNP: rs1554038048
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Degerman lab, Umeå University RCV000677348 SCV000611700 likely pathogenic Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 2017-11-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV005056102 SCV005726890 uncertain significance not specified 2024-11-08 criteria provided, single submitter clinical testing Variant summary: TERT c.3399A>G (p.X1133TrpextX39) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. The variant was absent in 239294 control chromosomes (gnomAD). c.3399A>G has been reported in the literature in heterozygous state in an individual affected with aplastic anemia, who had shorter telomere length and positive family history for pulmonary fibrosis (Norberg_2018); in this family the variant was also found in a heterozygous unaffected parent, who had telomeres within the lower normal range, however, variable penetrance is known for TERT-Related Disorders. These data do not allow clear conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, other variants affecting the C-terminal region of the protein (e.g. c.3346_*123del177 / p.Glu1116fsX, p.Phe1127Leu, p.Thr1129Pro, p.Ile1130Val) have been reported in affected individuals (HGMD), indicating the functional importance of this protein region. ClinVar contains an entry for this variant (Variation ID: 446375). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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