ClinVar Miner

Submissions for variant NM_198253.3(TERT):c.193C>G (p.Pro65Ala)

gnomAD frequency: 0.00003  dbSNP: rs544215765
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002530117 SCV000650719 likely benign Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis 2024-12-08 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV001254604 SCV001430615 likely pathogenic Dyskeratosis congenita, autosomal dominant 2 2020-07-20 criteria provided, single submitter clinical testing This TERT variant has been reported in patients presenting with cirrhosis and acute myeloid leukemia with aplastic anemia. Functional studies showed that this variant significantly reduces telomerase activity compared to the wildtype. TERT c.193C>G is located in the RNA-interaction domain within the N-terminal extension region. This variant (rs544215765) has a ClinVar entry, and is shown rare (<0.1%) in a large population dataset (gnomAD: 3/150704 total alleles; 0.002%; no homozygotes), however this frequency estimate may not be reliable due to low coverage at this position in gnomAD exomes. We consider this variant to be likely pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV001254604 SCV002512717 uncertain significance Dyskeratosis congenita, autosomal dominant 2 2022-02-11 criteria provided, single submitter clinical testing ACMG classification criteria: PS3 supporting, PS4 supporting, PP2 supporting, BP4 supporting
Sema4, Sema4 RCV002256385 SCV002533115 uncertain significance Dyskeratosis congenita 2021-12-20 criteria provided, single submitter curation
GeneDx RCV003236816 SCV003935762 uncertain significance not provided 2023-11-03 criteria provided, single submitter clinical testing Published functional studies are conflicting: some demonstrate reduced or absent telomerase activity and reduced cell growth compared to wildtype, while others failed to show significant reductions in telomerase activity and processivity (PMID: 19147845, 21520174, 23901009); Reported in the germline of individuals with aplastic anemia, myelodysplastic syndrome, and/or liver cirrhosis (PMID: 21520174, 30523342, 35969835); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30995915, 19796246, 19636400, 23901009, 19147845, 21520174, 23716176, 35969835, 30523342)
Baylor Genetics RCV001254604 SCV004208106 uncertain significance Dyskeratosis congenita, autosomal dominant 2 2023-10-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV002256385 SCV005512344 uncertain significance Dyskeratosis congenita 2024-12-05 criteria provided, single submitter clinical testing The p.P65A variant (also known as c.193C>G), located in coding exon 1 of the TERT gene, results from a C to G substitution at nucleotide position 193. The proline at codon 65 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.

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