rs1554121443

Positions:

• chr6-33438873-C-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.1630C>T​(p.Arg544Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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: 32)
• Consequence: SYNGAP1 NM_006772.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.591

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 6-33438873-C-T is Pathogenic according to our data. Variant chr6-33438873-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 522845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNGAP1	NM_006772.3	c.1630C>T	p.Arg544Ter	stop_gained	10/19	ENST00000646630.1
SYNGAP1-AS1	NR_174954.1	n.330-1392G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.1630C>T	p.Arg544Ter	stop_gained	10/19		NM_006772.3	P1
SYNGAP1-AS1	ENST00000630418.1	n.378-1392G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 01, 2022	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jun 16, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Dec 04, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2023	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: 31349857, 25326635, 26989088) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2021

The c.1630C>T (p.R544*) alteration, located in exon 10 (coding exon 10) of the SYNGAP1 gene, consists of a C to T substitution at nucleotide position 1630. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 544. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported to occur de novo in a patient with severe intellectual disability, truncal hypotonia, swallowing difficulties, epilepsy, and very poor social interactions (Mignot, 2016). In addition, this alteration has also been identified in a patient with generalized epilepsy (Hoelz, 2020) and in a mosaic patient with a neurodevelopmental phenotype (Cao, 2019). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.67	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.93, 0.94, 0.94, 0.93
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1554121443; hg19: chr6-33406650;