6-33440913-C-T

Variant names:

• chr6-33440913-C-T
• rs1060503386
• NM_006772.3:c.1861C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006772.3(SYNGAP1):​c.1861C>T​(p.Arg621*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SYNGAP1 NM_006772.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 4.02

Genes affected

SYNGAP1 (HGNC:11497): (synaptic Ras GTPase activating protein 1) This gene encodes a Ras GTPase activating protein that is a member of the N-methyl-D-aspartate receptor complex. The N-terminal domain of the protein contains a Ras-GAP domain, a pleckstrin homology domain, and a C2 domain that may be involved in binding of calcium and phospholipids. The C-terminal domain consists of a ten histidine repeat region, serine and tyrosine phosphorylation sites, and a T/SXV motif required for postsynaptic scaffold protein interaction. The encoded protein negatively regulates Ras, Rap and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking to the postsynaptic membrane to regulate synaptic plasticity and neuronal homeostasis. Allelic variants of this gene are associated with intellectual disability and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

SYNGAP1-AS1 (HGNC:53831): (SYNGAP1 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-33440913-C-T is Pathogenic according to our data. Variant chr6-33440913-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 411589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33440913-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.1861C>T	p.Arg621*	stop_gained	Exon 11 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.1861C>T	p.Arg621*	stop_gained	Exon 11 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.1861C>T	p.Arg621*	stop_gained	Exon 11 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.1861C>T	p.Arg621*	stop_gained	Exon 11 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.1861C>T	p.Arg621*	stop_gained	Exon 11 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.1684C>T	p.Arg562*	stop_gained	Exon 9 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Pathogenic:3 Other:1

Apr 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with SYNGAP1-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 411589). 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). -

Jul 10, 2019

Genetics Laboratory - UDIAT Centre Diagnòstic, Hospital Universitari Parc Tauli

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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/. -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Neurodevelopmental delay Pathogenic:1

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Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 05, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32472547, 34653234, 33090308, 30455457, 34924933, 28191889, 31440721, 31175295, 31395010) -

Complex neurodevelopmental disorder Pathogenic:1

Apr 06, 2018

GenomeConnect - Simons Searchlight

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-06 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.88	D
Vest4		0.96, 0.96, 0.94, 0.96
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060503386; hg19: chr6-33408690;