ClinVar Miner

Submissions for variant NM_198253.3(TERT):c.2286+1G>A

dbSNP: rs1749780301
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002675447 SCV002296004 likely pathogenic Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis 2024-01-11 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 6 of the TERT gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TERT are known to be pathogenic (PMID: 16247010, 17460043). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of familial pulmonary fibrosis (PMID: 30995915). ClinVar contains an entry for this variant (Variation ID: 1502782). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV004558797 SCV002735516 likely pathogenic Dyskeratosis congenita 2015-12-29 criteria provided, single submitter clinical testing The c.2286+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 6 of the TERT gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice donor site are typically deleterious in nature (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). As such, the c.2286+1G>A variant is classified as likely pathogenic.

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