NM_006772.3(SYNGAP1):c.490C>T (p.Arg164Ter) AND Intellectual disability, autosomal dominant 5

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Apr 18, 2023
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:: RCV000496106.18

Allele description [Variation Report for NM_006772.3(SYNGAP1):c.490C>T (p.Arg164Ter)]

NM_006772.3(SYNGAP1):c.490C>T (p.Arg164Ter)

Gene:

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.490C>T (p.Arg164Ter)

HGVS:

NC_000006.12:g.33432787C>T
NG_016137.2:g.17718C>T
NM_001130066.2:c.490C>T
NM_006772.3:c.490C>TMANE SELECT
NP_001123538.1:p.Arg164Ter
NP_006763.2:p.Arg164Ter
LRG_1193t1:c.490C>T
LRG_1193:g.17718C>T
LRG_1193p1:p.Arg164Ter
NC_000006.11:g.33400564C>T
NM_006772.2:c.490C>T

Protein change:

R164*

Links:

dbSNP: rs1057518352

NCBI 1000 Genomes Browser:

rs1057518352

Molecular consequence:

NM_001130066.2:c.490C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_006772.3:c.490C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Intellectual disability, autosomal dominant 5 (MRD5)
Synonyms:: INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 5
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
SCV000586776	Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 6, 2017)	de novo	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 28708303
SCV001380303	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 17, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 23161826, 23708187, 26989088, 28708303, 30541864, 28492532
SCV001523724	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 3, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002018919	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 8, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002587098	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 18, 2023)	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	1	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
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.

Carvill GL, Heavin SB, Yendle SC, McMahon JM, O'Roak BJ, Cook J, Khan A, Dorschner MO, Weaver M, Calvert S, Malone S, Wallace G, Stanley T, Bye AM, Bleasel A, Howell KB, Kivity S, Mackay MT, Rodriguez-Casero V, Webster R, Korczyn A, Afawi Z, et al.

Nat Genet. 2013 Jul;45(7):825-30. doi: 10.1038/ng.2646. Epub 2013 May 26.

PubMed [citation]

PMID:: 23708187
PMCID:: PMC3704157

See all PubMed Citations (7)

Details of each submission

From Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris, SCV000586776.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

Intellectual disability, severe; epilepsy; autism

#	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		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001380303.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change creates a premature translational stop signal (p.Arg164*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 373327). This premature translational stop signal has been observed in individual(s) with SYNGAP1-related conditions (PMID: 26989088, 28708303, 30541864). This variant is not present in population databases (gnomAD no frequency).

#	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 Baylor Genetics, SCV001523724.1

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

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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

From Revvity Omics, Revvity, SCV002018919.3

#	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 Institute of Human Genetics, University of Leipzig Medical Center, SCV002587098.2

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

Description

This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PVS1, PS2, PS4_MOD, PM2_SUP

#	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: Oct 20, 2024

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