ClinVar Miner

Submissions for variant NM_001111125.3(IQSEC2):c.2777G>A (p.Arg926Gln)

gnomAD frequency: 0.00002  dbSNP: rs1556861372
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000647966 SCV000769776 likely benign Intellectual disability, X-linked 1 2022-12-06 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001726290 SCV001962629 uncertain significance not provided 2021-09-01 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000647966 SCV002557888 uncertain significance 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 VUS-3C. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanism of disease in this gene and are associated with IQSEC2 -related intellectual disability (MIM# 309530). Loss of function has been demonstrated as the predominant disease mechanism for this gene, however some missense variants have been shown to impair GTP binding and cause the constitutively active protein activity (PMID: 20473311, PMID: 30842726). (I) 0110 - This gene is associated with X-linked disease. Males present with a severe early-onset condition, whereas females have a more variable phenotype, which tends be milder with a later onset, and they can also be asymptomatic carriers (PMID: 30206421). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0253 - This variant is hemizygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a X-linked condition (2 heterozygotes, 0 homozygotes, 1 hemizygote). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Sec7 domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has previously been classified as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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