Submissions for variant NM_006772.3(SYNGAP1):c.1717C>T (p.Arg573Trp)

dbSNP: rs1064795331

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483715	SCV000571030	pathogenic	not provided	2021-11-26	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30581057)
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000656412	SCV000778420	likely pathogenic	Intellectual disability, autosomal dominant 5	2017-04-13	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Strasbourg University Hospital	RCV001260776	SCV001437868	likely pathogenic	Intellectual disability	2020-09-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000656412	SCV002016837	likely pathogenic	Intellectual disability, autosomal dominant 5	2020-04-05	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000656412	SCV002058225	pathogenic	Intellectual disability, autosomal dominant 5	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been previously reported as de novo in a similarly affected individual (PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000421734, PMID:30581057, PS1_S).A different missense change at the same codon (p.Arg573Leu, p.Arg573Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000521291,VCV001176819, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.758, 3CNET: 0.862, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000656412	SCV004551594	uncertain significance	Intellectual disability, autosomal dominant 5	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 573 of the SYNGAP1 protein (p.Arg573Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SYNGAP1-related conditions (PMID: 30581057). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 421734). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SYNGAP1 protein function. 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000483715	SCV001978703	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000483715	SCV001979353	pathogenic	not provided		no assertion criteria provided	clinical testing