NM_006772.3(SYNGAP1):c.1630C>T (p.Arg544Ter) AND Intellectual disability, autosomal dominant 5

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jul 1, 2022
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:: RCV000626018.8

Allele description [Variation Report for NM_006772.3(SYNGAP1):c.1630C>T (p.Arg544Ter)]

NM_006772.3(SYNGAP1):c.1630C>T (p.Arg544Ter)

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.1630C>T (p.Arg544Ter)

HGVS:

NC_000006.12:g.33438873C>T
NG_016137.2:g.23804C>T
NM_001130066.2:c.1630C>T
NM_006772.3:c.1630C>TMANE SELECT
NP_001123538.1:p.Arg544Ter
NP_006763.2:p.Arg544Ter
LRG_1193t1:c.1630C>T
LRG_1193:g.23804C>T
LRG_1193p1:p.Arg544Ter
NC_000006.11:g.33406650C>T
NM_006772.2:c.1630C>T
p.R544X

Protein change:

R544*

Links:

dbSNP: rs1554121443

NCBI 1000 Genomes Browser:

rs1554121443

Molecular consequence:

NM_001130066.2:c.1630C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_006772.3:c.1630C>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
SCV000746627	Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 16, 2017)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000807555	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2017)	de novo	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 25326635
SCV000996221	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 4, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001209200	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 1, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23161826, 23708187, 26989088, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
White	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular findings among patients referred for clinical whole-exome sequencing.

Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, Ward P, Braxton A, Wang M, Buhay C, Veeraraghavan N, Hawes A, Chiang T, Leduc M, Beuten J, Zhang J, He W, Scull J, Willis A, Landsverk M, Craigen WJ, Bekheirnia MR, et al.

JAMA. 2014 Nov 12;312(18):1870-9. doi: 10.1001/jama.2014.14601.

PubMed [citation]

PMID:: 25326635
PMCID:: PMC4326249

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

See all PubMed Citations (6)

Details of each submission

From Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV000746627.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	White	1	not provided	not provided	clinical testing (GTR000553916.1)	PubMed (1)

Description

A mosaic c.1630C>T (p.R544X) pathogenic variant in the SYNGAP1 gene was detected in this individual (33 mutant and 256 reference reads) and was confirmed by Sanger sequencing. This variant has been previously reported as de novo in a patient with intellectual disability and developmental delay (PMID: 26989088) and is predicted to result in a premature stop codon.

#	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	(GTR000553916.1)	1	not provided	not provided	not provided

From Baylor Genetics, SCV000807555.2

#	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 de novo in an 11-year-old female with Leigh disease, intellectual disability, short stature, microcephaly, failure to thrive, PDA, brachydactyly, pes planus, congenital hypothyroidism. Patient also carried compound heterozygous pathogenic variants in MTFMT.

#	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	(GTR000508680.4)	not provided	not provided	not provided	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV000996221.1

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

Description

This nonsense variant found in exon 10 of 19 is predicted to result in loss of normal protein function. This variant has been previously reported as a de novo change in a patient with global developmental delay and epilepsy (PMID: 26989088). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.1630C>T (p.Arg544Ter) variant is classified as pathogenic.

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

From Invitae, SCV001209200.3

#	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: 522845). This premature translational stop signal has been observed in individual(s) with infantile epileptic encephalopathy (PMID: 26989088). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg544*) 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

Last Updated: May 12, 2024

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