ClinVar Miner

Submissions for variant NM_006772.3(SYNGAP1):c.1676+1G>A

dbSNP: rs2151172748
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV001822991 SCV002072487 pathogenic SYNGAP1-related encephalopathy 2022-01-30 criteria provided, single submitter clinical testing
Invitae RCV001869805 SCV002285442 likely pathogenic Intellectual disability, autosomal dominant 5 2021-07-14 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV001869805 SCV002766726 likely pathogenic Intellectual disability, autosomal dominant 5 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with SYNGAP1 -related intellectual disability. While loss of function is established for protein truncating variants, it is also a likely mechanism of disease for missense variants although a dominant-negative mechanism of disease cannot be excluded (PMIDs: 23161826, 26079862). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0703 - Other splice variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. A de novo c. 1676 + 2T>C canonical splice site variant was identified in an individual with intellectual disability and a de novo c.1676+5 G>A splice region variant was identified in an individual with severe intellectual disability, epilepsy and autistic features. RT-PCR of patient cDNA carrying the latter demonstrated activation of a crytic donor site 37bp upstream of the WT donor site, resulting in a frameshift and premature stop codon (PMIDs: 28333917, 28576131). (SP) 0807 - This variant has no previous evidence of pathogenicity. (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) 1102 - Strong phenotype match for this individual. (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV001869805 SCV004014000 pathogenic Intellectual disability, autosomal dominant 5 2021-12-09 criteria provided, single submitter clinical testing PVS1, PS2, PM2, PP3

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