NM_006772.3(SYNGAP1):c.1676+1G>A AND Intellectual disability, autosomal dominant 5

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 9, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001869805.7

Allele description [Variation Report for NM_006772.3(SYNGAP1):c.1676+1G>A]

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

Genes:

SYNGAP1-AS1:SYNGAP1 antisense RNA 1 [Gene - HGNC]
SYNGAP1:synaptic Ras GTPase activating protein 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p21.32

Genomic location:

Preferred name:

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

HGVS:

NC_000006.12:g.33438920G>A
NG_016137.2:g.23851G>A
NM_001130066.2:c.1676+1G>A
NM_006772.3:c.1676+1G>AMANE SELECT
LRG_1193t1:c.1676+1G>A
LRG_1193:g.23851G>A
NC_000006.11:g.33406697G>A
NM_006772.2:c.1676+1G>A

Links:

dbSNP: rs2151172748

NCBI 1000 Genomes Browser:

rs2151172748

Molecular consequence:

NM_001130066.2:c.1676+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_006772.3:c.1676+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Intellectual disability, autosomal dominant 5 (MRD5)
Synonyms:: Mental retardation, autosomal dominant 5; INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 5; SYNGAP1-related developmental and epileptic encephalopathy
Identifiers:: MONDO: MONDO:0012960; MedGen: C2675473; OMIM: 612621

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002285442	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 14, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002766726	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 6, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23161826, 26079862, 28333917, 28576131, 25741868
SCV004014000	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 9, 2021)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002285442

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 14, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002766726

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 6, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004014000

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 9, 2021)

de novo

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency.

Berryer MH, Hamdan FF, Klitten LL, Møller RS, Carmant L, Schwartzentruber J, Patry L, Dobrzeniecka S, Rochefort D, Neugnot-Cerioli M, Lacaille JC, Niu Z, Eng CM, Yang Y, Palardy S, Belhumeur C, Rouleau GA, Tommerup N, Immken L, Beauchamp MH, Patel GS, Majewski J, et al.

Hum Mutat. 2013 Feb;34(2):385-94. doi: 10.1002/humu.22248. Epub 2012 Dec 12.

PubMed [citation]

PMID:: 23161826

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002285442.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002766726.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV004014000.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PVS1, PS2, PM2, PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 13, 2025

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