Submissions for variant NM_000460.4(THPO):c.13+2T>C

dbSNP: rs1714390786

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clinical Genomics Program, Stanford Medicine	RCV001252954	SCV001427017	likely pathogenic	Thrombocythemia 1	2018-10-15	no assertion criteria provided	clinical testing	The c.13+2T>C variant in the THPO gene has been previously reported in this family and co-segregated with disease in 3 affected relatives (Zhang et al., 2011). The c.13+2T>C variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The c.13+2T>C variant alters the canonical donor splice site in intron 3, which is predicted to result in abnormal gene splicing. Well-established in vitro functional studies strongly support this variant causing a splice defect (Zhang et al., 2011). Additionally, a different nucleotide change, c.13+1G>C, disrupting the same canonical splice site has been previously reported (Wiestner et al., 1998). The c.13+1G>C variant is classified as pathogenic and is expected to result in a similar disruption to protein function as c. 13+2T>C. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the variant as likely pathogenic for thrombocythemia in an autosomal dominant manner based on the information above [ACMG evidence codes used: PS3, PM2_supporting, PP1].