ClinVar Miner

Submissions for variant NM_015559.3(SETBP1):c.487-1G>A

gnomAD frequency: 0.00007  dbSNP: rs147805077
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494550 SCV000582113 uncertain significance not provided 2020-07-24 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in an in-frame deletion exon 3; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29625052)
New York Genome Center RCV001706646 SCV001815700 uncertain significance Intellectual disability, autosomal dominant 29 2020-09-23 criteria provided, single submitter clinical testing The inherited heterozygous c.487-1G>A splice site variant identified in the SETBP1 gene is located in intron 2 of 5 (at intron 2/exon 3 splice site). It destroys the canonical splice acceptor site and is predicted to cause abnormal splicing of SETBP1mRNA. This variant has been reported in ClinVar database as likely pathogenic (ClinVar ID: 429524). The variant has also been reported in a patient with ovarian serous cystadenocarcinoma with no mention of aneurological abnormality [PMID: 29625052]. The c.487-1G>A variant has 0.00005913 allele frequency in the gnomAD(v3) database (9 out of 152,212 heterozygous alleles). Given that the variant is inherited from asymptomatic parent, its presence in multiple individuals in gnomAD database which presumably doesn’t include patients affected with early onset disorders, lack of sufficient evidence of reduced penetrance, and in the absence of any functional studies, we interpret the c.487-1G>A splice site variant as a variant of uncertain significance in the context of an early onset neurological disorder.
Labcorp Genetics (formerly Invitae), Labcorp RCV000494550 SCV002255174 likely pathogenic not provided 2025-01-27 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 2 of the SETBP1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SETBP1 are known to be pathogenic (PMID: 21037274, 25217958). This variant is present in population databases (rs147805077, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SETBP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 429524). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV001706646 SCV003806894 uncertain significance Intellectual disability, autosomal dominant 29 2022-04-29 criteria provided, single submitter clinical testing ACMG classification criteria: PP3 supporting

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