NM_006772.3(SYNGAP1):c.2197C>T (p.Gln733Ter) AND Intellectual disability, autosomal dominant 5

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 17, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004594368.1

Allele description [Variation Report for NM_006772.3(SYNGAP1):c.2197C>T (p.Gln733Ter)]

NM_006772.3(SYNGAP1):c.2197C>T (p.Gln733Ter)

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.2197C>T (p.Gln733Ter)

HGVS:

NC_000006.12:g.33441662C>T
NG_016137.2:g.26593C>T
NM_001130066.2:c.2197C>T
NM_006772.3:c.2197C>TMANE SELECT
NP_001123538.1:p.Gln733Ter
NP_006763.2:p.Gln733Ter
LRG_1193t1:c.2197C>T
LRG_1193:g.26593C>T
LRG_1193p1:p.Gln733Ter
NC_000006.11:g.33409439C>T
NM_006772.2:c.2197C>T

Protein change:

Q733*

Links:

dbSNP: rs1554121924

NCBI 1000 Genomes Browser:

rs1554121924

Molecular consequence:

NM_001130066.2:c.2197C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_006772.3:c.2197C>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005086889	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29346770, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005086889

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 17, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Citations

PubMed

Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder.

Takata A, Miyake N, Tsurusaki Y, Fukai R, Miyatake S, Koshimizu E, Kushima I, Okada T, Morikawa M, Uno Y, Ishizuka K, Nakamura K, Tsujii M, Yoshikawa T, Toyota T, Okamoto N, Hiraki Y, Hashimoto R, Yasuda Y, Saitoh S, Ohashi K, Sakai Y, et al.

Cell Rep. 2018 Jan 16;22(3):734-747. doi: 10.1016/j.celrep.2017.12.074.

PubMed [citation]

PMID:: 29346770

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086889.1

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

Description

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) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by a clinical laboratory in ClinVar, and was observed as de novo in an individual with autism (PMID: 29346770). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 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

#	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		not provided	not provided	not provided	not provided

Last Updated: Aug 4, 2024

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