NM_000171.4(GLRA1):c.801G>T (p.Trp267Cys) AND Hereditary hyperekplexia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 7, 2024
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:: RCV003596371.1

Allele description [Variation Report for NM_000171.4(GLRA1):c.801G>T (p.Trp267Cys)]

NM_000171.4(GLRA1):c.801G>T (p.Trp267Cys)

Gene:

GLRA1:glycine receptor alpha 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q33.1

Genomic location:

Preferred name:

NM_000171.4(GLRA1):c.801G>T (p.Trp267Cys)

HGVS:

NC_000005.10:g.151851501C>A
NG_011764.1:g.78336G>T
NM_000171.4:c.801G>TMANE SELECT
NM_001146040.2:c.801G>T
NM_001292000.2:c.552G>T
NP_000162.2:p.Trp267Cys
NP_001139512.1:p.Trp267Cys
NP_001278929.1:p.Trp184Cys
NC_000005.9:g.151231062C>A

Protein change:

W184C

Molecular consequence:

NM_000171.4:c.801G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001146040.2:c.801G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001292000.2:c.552G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary hyperekplexia
Synonyms:: Hyperexplexia, hereditary
Identifiers:: MONDO: MONDO:0021022; MedGen: C1835614; OMIM: PS149400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004261296	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 7, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15771552, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004261296

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 7, 2024)

germline

clinical testing

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

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

Citations

PubMed

Hereditary hyperekplexia caused by novel mutations of GLRA1 in Turkish families.

Gilbert SL, Ozdag F, Ulas UH, Dobyns WB, Lahn BT.

Mol Diagn. 2004;8(3):151-5.

PubMed [citation]

PMID:: 15771552

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

Details of each submission

From Invitae, SCV004261296.1

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

Description

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 267 of the GLRA1 protein (p.Trp267Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperekplexia (PMID: 15771552). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLRA1 protein function with a positive predictive value of 95%. 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.

#	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: Feb 20, 2024

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