NM_005639.3(SYT1):c.1098C>G (p.Asp366Glu) AND Syndromic intellectual disability

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 28, 2020
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:: RCV001254686.2

Allele description [Variation Report for NM_005639.3(SYT1):c.1098C>G (p.Asp366Glu)]

NM_005639.3(SYT1):c.1098C>G (p.Asp366Glu)

Gene:

SYT1:synaptotagmin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q21.2

Genomic location:

Preferred name:

NM_005639.3(SYT1):c.1098C>G (p.Asp366Glu)

HGVS:

NC_000012.12:g.79448953C>G
NM_001135805.2:c.1098C>G
NM_001135806.2:c.1098C>G
NM_001291901.2:c.1089C>G
NM_005639.3:c.1098C>GMANE SELECT
NP_001129277.1:p.Asp366Glu
NP_001129278.1:p.Asp366Glu
NP_001278830.1:p.Asp363Glu
NP_005630.1:p.Asp366Glu
NC_000012.11:g.79842733C>G

Protein change:

D363E

Links:

dbSNP: rs1565962725

NCBI 1000 Genomes Browser:

rs1565962725

Molecular consequence:

NM_001135805.2:c.1098C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001135806.2:c.1098C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001291901.2:c.1089C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_005639.3:c.1098C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Syndromic intellectual disability
Synonyms:: Intellectual disability syndrome
Identifiers:: MONDO: MONDO:0000508; MedGen: C5680525

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001430749	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 28, 2020)	germline	research	PubMed (2) [See all records that cite these PMIDs] 30107533, 25741868 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001430749

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 28, 2020)

germline

research

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

Citation Link

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	research

Citations

PubMed

SYT1-associated neurodevelopmental disorder: a case series.

Baker K, Gordon SL, Melland H, Bumbak F, Scott DJ, Jiang TJ, Owen D, Turner BJ, Boyd SG, Rossi M, Al-Raqad M, Elpeleg O, Peck D, Mancini GMS, Wilke M, Zollino M, Marangi G, Weigand H, Borggraefe I, Haack T, Stark Z, Sadedin S; et al.

Brain. 2018 Sep 1;141(9):2576-2591. doi: 10.1093/brain/awy209.

PubMed [citation]

PMID:: 30107533
PMCID:: PMC6113648

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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001430749.1

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

Description

The heterozygous p.Asp366Glu variant in SYT1 was identified by our study in an individual with Baker-Gordon syndrome (BAGOS) (PMID: 30107533). Trio exome analysis showed this variant to be de novo. This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Asp366Glu variant may slightly impact protein function through disruptions in exocytosis (PMID: 30107533). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional likely pathogenic variant, inducing the same amino acid change as this variant, has been reported in association with Baker-Gordon syndrome in the literature, slightly supporting that this variant may be pathogenic (PMID: 30107533). The p.Asp366Glu variant is located in a region of SYT1 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 30107533). In summary, this variant meets criteria to be classified as pathogenic for Baker-Gordon syndrome. ACMG/AMP Criteria applied: PS2, PM2, PS1_moderate, PM1_supporting, PS3_supporting (Richards 2015).

#	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: Dec 14, 2024

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