NM_006772.3(SYNGAP1):c.1861C>T (p.Arg621Ter) AND Intellectual disability, autosomal dominant 5

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Apr 1, 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:: RCV000470395.10

Allele description [Variation Report for NM_006772.3(SYNGAP1):c.1861C>T (p.Arg621Ter)]

NM_006772.3(SYNGAP1):c.1861C>T (p.Arg621Ter)

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.1861C>T (p.Arg621Ter)

HGVS:

NC_000006.12:g.33440913C>T
NG_016137.2:g.25844C>T
NM_001130066.2:c.1861C>T
NM_006772.3:c.1861C>TMANE SELECT
NP_001123538.1:p.Arg621Ter
NP_006763.2:p.Arg621Ter
LRG_1193t1:c.1861C>T
LRG_1193:g.25844C>T
LRG_1193p1:p.Arg621Ter
NC_000006.11:g.33408690C>T
NM_006772.2:c.1861C>T

Protein change:

R621*

Links:

dbSNP: rs1060503386

NCBI 1000 Genomes Browser:

rs1060503386

Molecular consequence:

NM_001130066.2:c.1861C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_006772.3:c.1861C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Intellectual disability, autosomal dominant 5 (MRD5)
Synonyms:: INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 5
Identifiers:: MONDO: MONDO:0012960; MedGen: C2675473; OMIM: 612621

Recent activity

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rab-like protein 2A isoform X10 [Homo sapiens]
rab-like protein 2A isoform X10 [Homo sapiens]
gi|2217325185|ref|XP_047299014.1|

Protein
G patch domain and ankyrin repeat-containing protein 1 isoform X1 [Homo sapiens]
G patch domain and ankyrin repeat-containing protein 1 isoform X1 [Homo sapiens]
gi|2462492581|ref|XP_054185875.1|

Protein
Abnormal lower limb epiphysis morphology
Abnormal lower limb epiphysis morphology

MedGen

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000552817	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 1, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23161826, 23708187, 26989088, 28492532
SCV000807317	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 25326635
SCV000930695	Genetics Laboratory - UDIAT Centre Diagnòstic, Hospital Universitari Parc Tauli	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 10, 2019)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004804631	GenomeConnect - Brain Gene Registry	no classification provided	not provided	unknown	phenotyping only

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	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
not provided	unknown	yes	1	not provided	not provided	1	not provided	phenotyping only
not provided	de novo	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 (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000552817.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 411589). This variant has not been reported in the literature in individuals affected with SYNGAP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg621*) 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).

#	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, SCV000807317.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing (GTR000508680.4)	PubMed (2)

Description

This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory in a 7-year-old male with global delays, autistic spectrum, seizure disorder, Chiari I malformation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided	(GTR000508680.4)	not provided	not provided	not provided	not provided

From Genetics Laboratory - UDIAT Centre Diagnòstic, Hospital Universitari Parc Tauli, SCV000930695.1

#	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	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GenomeConnect - Brain Gene Registry, SCV004804631.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	phenotyping only	not provided

Description

Variant classified as Pathogenic and reported on 03-22-2018 by MedGenome. 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/.

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

Last Updated: Sep 29, 2024

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