ClinVar Miner

Submissions for variant NM_198253.3(TERT):c.2221G>A (p.Val741Met) (rs150819225)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000539480 SCV000650737 uncertain significance Idiopathic fibrosing alveolitis, chronic form; Dyskeratosis congenita, autosomal dominant, 2 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 741 of the TERT protein (p.Val741Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs150819225, ExAC 0.02%). This variant has not been reported in the literature in individuals with TERT-related conditions. ClinVar contains an entry for this variant (Variation ID: 471857). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768106 SCV000899021 uncertain significance Acute myeloid leukemia; Dyskeratosis congenita, autosomal dominant, 2; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1; Cutaneous malignant melanoma 9 2018-08-07 criteria provided, single submitter clinical testing TERT NM_198253.2 exon 6 p.Val741Met (c.2221G>A): This variant has not been reported in the literature, but it is present in 3/24032 of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/5-1278821-C-T). This variant is present in ClinVar (Variation ID: 471857). This variant amino acid, Methionine (Met), is present in three mammalian species (Gorilla, Pika, Panda) and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant are insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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