Submissions for variant NM_015450.3(POT1):c.547-3C>A

gnomAD frequency: 0.00001  dbSNP: rs770890978

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000652208	SCV000774076	uncertain significance	Tumor predisposition syndrome 3	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change falls in intron 8 of the POT1 gene. It does not directly change the encoded amino acid sequence of the POT1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 541866). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in intron inclusion and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.
GeneDx	RCV001766415	SCV001990461	uncertain significance	not provided	2019-07-22	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago	RCV001816635	SCV002066861	uncertain significance	not specified	2021-02-24	criteria provided, single submitter	clinical testing	DNA sequence analysis of the POT1 gene demonstrated a sequence change in intron 8, c.547-3C>A. This intronic change is absent from known population databases (gnomAD). In-silico splice prediction programs suggest that this sequence change may disrupt the consensus splice site, however functional studies have not been performed to confirm this. The functional significance of this sequence change is not known at present and its contribution to this patient's disease phenotype cannot definitively be determined.
Ambry Genetics	RCV002343376	SCV002648166	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-31	criteria provided, single submitter	clinical testing	The c.547-3C>A intronic variant results from a C to A substitution 3 nucleotides before coding exon 5 in the POT1 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.