Submissions for variant NM_015559.3(SETBP1):c.2984C>T (p.Pro995Leu)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Medical Genetics, University of Torino	RCV002465468	SCV002760163	likely pathogenic	Intellectual disability, autosomal dominant 29	2022-11-29	criteria provided, single submitter	research
Neuberg Centre For Genomic Medicine, NCGM	RCV004577020	SCV005060997	uncertain significance	Schinzel-Giedion syndrome		criteria provided, single submitter	clinical testing	The missense c.2984C>T (p.Pro995Leu) variant in the SETBP1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is absent in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic. However, no details are available for independent assessment. The amino acid Proline at position 995 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Pro995Leu in SETBP1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700765	SCV005203043	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing	Variant summary: SETBP1 c.2984C>T (p.Pro995Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251394 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2984C>T has been reported in the literature in at least an individual affected with autism spectrum disorder (example: Fu_2022). These report(s) do not provide unequivocal conclusions about association of the variant with SETBP1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35982160). ClinVar contains an entry for this variant (Variation ID: 1802629). Based on the evidence outlined above, the variant was classified as uncertain significance.