Submissions for variant NM_006772.3(SYNGAP1):c.3583-6G>A

dbSNP: rs869312674

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000209920	SCV000265528	likely pathogenic	Intellectual disability, autosomal dominant 5	2025-01-21	criteria provided, single submitter	research
Diagnostic Laboratory, Strasbourg University Hospital	RCV000224644	SCV000281748	pathogenic	Intellectual disability	2014-07-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000209920	SCV000824390	pathogenic	Intellectual disability, autosomal dominant 5	2024-05-15	criteria provided, single submitter	clinical testing	This sequence change falls in intron 16 of the SYNGAP1 gene. It does not directly change the encoded amino acid sequence of the SYNGAP1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with SYNGAP1-related conditions (PMID: 25167861, 28554332). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 224094). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001778797	SCV002015747	pathogenic	not provided	2024-02-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28524815, 28721930, 25167861, 28554332, 33639450, 34070602)
MGZ Medical Genetics Center	RCV000209920	SCV002579818	likely pathogenic	Intellectual disability, autosomal dominant 5	2021-12-14	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000209920	SCV003925634	likely pathogenic	Intellectual disability, autosomal dominant 5	2023-04-05	criteria provided, single submitter	clinical testing	Criteria applied: PS2,PS4_MOD,PM2_SUP
PreventionGenetics, part of Exact Sciences	RCV004547504	SCV004106056	pathogenic	SYNGAP1-related disorder	2023-05-23	criteria provided, single submitter	clinical testing	The SYNGAP1 c.3583-6G>A variant is predicted to interfere with splicing. This variant has been reported in the heterozygous, de novo state in an individual with intellectual disability (APN-139; Figure S8 and Table S9, Redin et al. 2014. PubMed ID: 25167861), an individual with intellectual disability (moderate), autism spectrum disorder, speech delay and seizures (Table S2, Bowling et al. 2017. PubMed ID: 28554332), and in an individual with autism, severe cognitive disability, nystagmus, feeding issues, aspecific white matter hypersignal, seizures, and no speech (Patient ID 8, Lo Barco et al. 2021. PubMed ID: 33639450). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000209920	SCV005086900	pathogenic	Intellectual disability, autosomal dominant 5	2023-07-17	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: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intellectual developmental disorder 5 (MIM#612621). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). mRNA analysis from an affected individual describes this variant as resulting in the formation of a cryptic acceptor site, and a frameshift outcome (p.Val1195Alafs*27)). However, no mRNA data or results were shown (PMID: 25167861). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0311 - An alternative nucleotide change at the same canonical splice site, is present in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0505 - Abnormal splicing in silico tools were inconclusive and affected nucleotide is highly conserved. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported once as a VUS (PMID: 28554332), but moreso as likely pathogenic and pathogenic, and observed de novo in several individuals with features including global developmental delay, intellectual disability and hypotonia (PMID: 25167861, PMID: 30800045, PMID: 33639450). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign