Submissions for variant NM_015450.3(POT1):c.9+4A>C

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003746813	SCV004389242	pathogenic	Tumor predisposition syndrome 3	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change falls in intron 5 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 is likely to result in the loss of the initiator methionine. 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. 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 skipping of exon 5, and is expected to result in the loss of the initiator methionine (Invitae). This variant disrupts a region of the POT1 protein in which other variant(s) (p.Arg117Cys) have been determined to be pathogenic (PMID: 26403419; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.