NM_006950.3(SYN1):c.1321G>A (p.Ala441Thr) AND Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 24, 2021
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:: RCV001857173.9

Allele description [Variation Report for NM_006950.3(SYN1):c.1321G>A (p.Ala441Thr)]

NM_006950.3(SYN1):c.1321G>A (p.Ala441Thr)

Gene:

SYN1:synapsin I [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp11.3

Genomic location:

Preferred name:

NM_006950.3(SYN1):c.1321G>A (p.Ala441Thr)

HGVS:

NC_000023.11:g.47574760C>T
NG_008437.1:g.50098G>A
NM_006950.3:c.1321G>AMANE SELECT
NM_133499.2:c.1321G>A
NP_008881.2:p.Ala441Thr
NP_598006.1:p.Ala441Thr
NC_000023.10:g.47434159C>T
NM_006950.3:c.1321G>A

Protein change:

A441T

Links:

dbSNP: rs772106134

NCBI 1000 Genomes Browser:

rs772106134

Molecular consequence:

NM_006950.3:c.1321G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133499.2:c.1321G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders
Synonyms:: Epilepsy, X-linked, with variable learning disabilities and behavior disorders; X-linked epilepsy-learning disabilities-behavior disorders syndrome
Identifiers:: MONDO: MONDO:0010339; MedGen: C5774177; Orphanet: 85294; OMIM: 300491

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002119782	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 24, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004046906	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002119782

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 24, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004046906

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

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 Invitae, SCV002119782.3

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SYN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 436901). This variant is present in population databases (rs772106134, ExAC 0.05%). This sequence change replaces alanine with threonine at codon 441 of the SYN1 protein (p.Ala441Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine.

#	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

From Neuberg Centre For Genomic Medicine, NCGM, SCV004046906.1

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

Description

The missense c.1321G>A (p.Ala441Thr) variant in SYN1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.0007% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar as Uncertain Significance. The amino acid Ala at position 441 is changed to a Thr changing protein sequence and it might alter its composition and physicochemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Ala441Thr in SYN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. The observed variant was detected in hemizygous state in the brother.

#	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: May 1, 2024

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