Submissions for variant NM_015559.3(SETBP1):c.2607C>G (p.Ser869Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV003315119	SCV004014699	pathogenic	Schinzel-Giedion syndrome	2023-01-24	criteria provided, single submitter	clinical testing	The SETBP1 c.2607C>G (p.Ser869Arg) missense variant results in the substitution of serine at amino acid position 869 with arginine. This variant has been reported in a heterozygous de novo state in one individual with Schinzel-Giedion syndrome (SGS) (PMID: 28346496). Two other variants at the same amino acid position, p.Ser869Asn and p.Ser869Gly, have been reported in patients with SGS (PMID: 28346496; PMID: 36147799). SGS is associated with de novo variants clustering in a 12 base pair hotspot of exon 4 that encodes amino acids in the SKI homologous region of the SETBP1 protein (D868, S869, G870, and I871), which constitute the degron degradation sequence (PMID: 28346496; PMID: 36147799). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database and was identified in a de novo state. Based on the available evidence, the c.2607C>G (p.Ser869Arg) variant is classified as pathogenic for Schinzel-Giedion syndrome.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701034	SCV005204836	likely pathogenic	SETBP1-related disorder	2024-06-10	criteria provided, single submitter	clinical testing	Variant summary: SETBP1 c.2607C>G (p.Ser869Arg) 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 251044 control chromosomes. c.2607C>G , arising de novo, has been reported in the literature in one individual affected with Schinzel-Giedion syndrome (Acuna-Hidalgo_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Additionally, at least one variant at the Ser869 residue has been reported as associated with disease (p.S869N), suggesting that this codon is functionally important. The following publication has been ascertained in the context of this evaluation (PMID: 28346496). ClinVar contains an entry for this variant (Variation ID: 2573005). Based on the evidence outlined above, the variant was classified as likely pathogenic.