Submissions for variant NM_006772.3(SYNGAP1):c.3718C>T (p.Arg1240Ter)

dbSNP: rs869312955

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000210697	SCV000262979	pathogenic	Inborn genetic diseases	2023-08-31	criteria provided, single submitter	clinical testing	The c.3718C>T (p.R1240*) alteration, located in exon 17 (coding exon 17) of the SYNGAP1 gene, consists of a C to T substitution at nucleotide position 3718. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 1240. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals with features consistent with SYNGAP1-related neurodevelopmental disorder, including multiple cases of reported de novo occurrence (Jang, 2019; Jimenez-Gomez, 2019; Truty, 2019; Vlaskamp, 2019; Bruno, 2021; Layne, 2022). One publication showed that the p.R1240* alteration retained 88% of wildtype protein stability and localized to aberrant, smaller cytoplasmic speckles compared to the wildtype (Meili, 2021). Another publication demonstrated that human induced pluripotent stem cell-derived neurons with this alteration exhibited a significant reduction in SYNGAP1 mRNA and protein compared to control lines (Dawicki-McKenna, 2023). Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV000679896	SCV000807319	pathogenic	Intellectual disability, autosomal dominant 5	2017-09-01	criteria provided, single submitter	clinical testing	This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in a 4-year-old male with global delays & mild hypotonia.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000679896	SCV000812402	pathogenic	Intellectual disability, autosomal dominant 5	2021-09-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000760502	SCV000890393	pathogenic	not provided	2022-02-08	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26795593, 25356970, 30541864, 30455457, 31395010, 28191889, 33308442)
Fulgent Genetics, Fulgent Genetics	RCV000679896	SCV000893717	pathogenic	Intellectual disability, autosomal dominant 5	2018-10-31	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000679896	SCV001976803	pathogenic	Intellectual disability, autosomal dominant 5	2021-10-05	criteria provided, single submitter	clinical testing	PVS1, PM2, PP3, PP5
Institute of Human Genetics, University of Leipzig Medical Center	RCV000679896	SCV004242428	pathogenic	Intellectual disability, autosomal dominant 5	2023-12-12	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS2,PS4_MOD,PM2_SUP
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000679896	SCV005086082	pathogenic	Intellectual disability, autosomal dominant 5	2023-12-21	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, autosomal dominant 5 (MIM#612621). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (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. (DECIPHER) (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported six times as likely pathogenic and pathogenic (ClinVar), and at least twice as de novo. Affected individuals included a child with developmental delay and gait disturbance (PMID: 35814954), a de novo case with epilepsy (PMID: 31572294), and another individual with epilepsy and severe developmental impairment (PMID:31395010). (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
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000760502	SCV005198381	pathogenic	not provided	2023-03-27	criteria provided, single submitter	clinical testing
GenomeConnect - Simons Searchlight	RCV001265530	SCV001443674	pathogenic	Complex neurodevelopmental disorder	2014-11-18	no assertion criteria provided	provider interpretation	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2014-11-18 and interpreted as Pathogenic. Variant was initially reported on 2012-12-06 by GTR ID of laboratory name 1006. The reporting laboratory might also submit to ClinVar.
GenomeConnect - Brain Gene Registry	RCV000679896	SCV004804539	not provided	Intellectual disability, autosomal dominant 5		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 12-06-2012 by Baylor College of Medicine. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.