ClinVar Miner

Submissions for variant NM_001111125.3(IQSEC2):c.3279G>A (p.Ser1093=)

dbSNP: rs1602260263
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000850562 SCV000992777 likely pathogenic Intellectual disability, X-linked 1 2017-12-31 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001091935 SCV001248225 likely pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
GeneDx RCV001091935 SCV001778263 pathogenic not provided 2023-09-26 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 31216405)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000850562 SCV002767235 pathogenic Intellectual disability, X-linked 1 2022-02-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with X-linked intellectual disability 1/78 (MIM#309530). Missense variants have been demonstrated to impair GTP binding and cause the constitutively active protein activity (PMID: 20473311, PMID: 30842726). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variants results in the use of a cryptic acceptor site, leading to the formation of a premature termination codon (p.(Ser1093*)). This protein outcome is expected to result in nonsense-mediated decay (Splicing Diagnostics, Kids Neuroscience Centre). (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. This variants have been reported many times as pathogenic, in both affected males and females (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic, and observed in an individual with intellectual disability (ClinVar, PMID: 30206421). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Invitae RCV000850562 SCV002964668 uncertain significance Intellectual disability, X-linked 1 2023-04-24 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 689766). This variant has not been reported in the literature in individuals affected with IQSEC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 1093 of the IQSEC2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the IQSEC2 protein.

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