Submissions for variant NM_006772.3(SYNGAP1):c.1167_1168del (p.Gly391fs)

dbSNP: rs1060503378

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457705	SCV000552781	pathogenic	Intellectual disability, autosomal dominant 5	2024-02-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly391Glnfs*27) in the SYNGAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SYNGAP1 are known to be pathogenic (PMID: 23161826, 23708187, 26989088). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of SYNGAP1-related conditions (PMID: 30455457, 30541864, 31395010, 33639450). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 411566). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000482994	SCV000574296	pathogenic	not provided	2024-06-08	criteria provided, single submitter	clinical testing	Frameshift 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32593896, 30455457, 31395010, 33639450, 34580403, 31440721, 34924933, 38505260, 33057194, 35982159, 38045990, 30541864, 25326635)
Baylor Genetics	RCV000457705	SCV000807316	pathogenic	Intellectual disability, autosomal dominant 5	2017-09-01	criteria provided, single submitter	clinical testing	This frameshift variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in a 10-year-old female with global delays, cerebellar ataxia, autsim, ptosis.
Revvity Omics, Revvity	RCV000457705	SCV002018916	pathogenic	Intellectual disability, autosomal dominant 5	2023-10-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004022880	SCV004961433	pathogenic	Inborn genetic diseases	2023-11-27	criteria provided, single submitter	clinical testing	The c.1167_1168delAG (p.G391Qfs*27) alteration, located in coding exon 8 of the SYNGAP1 gene, consists of a deletion of 2 nucleotides from position 1167 to 1168, causing a translational frameshift with a predicted alternate stop codon after 27 amino acids. 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 variant has been reported in multiple children with seizures and cognitive impairment (Jimenez-Gomez, 2019; Pode-Shakked, 2021). Based on the available evidence, this alteration is classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000457705	SCV005086084	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 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 many times as pathogenic and once as likely pathogenic (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics, University of Leipzig Medical Center	RCV000457705	SCV005627530	pathogenic	Intellectual disability, autosomal dominant 5	2024-12-12	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS2_VSTR,PS4,PM2
Pediatric Genetics Clinic, Sheba Medical Center	RCV000457705	SCV001712233	pathogenic	Intellectual disability, autosomal dominant 5	2021-05-13	no assertion criteria provided	clinical testing
Molecular Genetics laboratory, Necker Hospital	RCV000482994	SCV004031320	likely pathogenic	not provided	2018-07-16	no assertion criteria provided	clinical testing