NM_000171.4(GLRA1):c.1325G>A (p.Arg442His) AND Hereditary hyperekplexia

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 18, 2023
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:: RCV001312216.4

Allele description

NM_000171.4(GLRA1):c.1325G>A (p.Arg442His)

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.1325G>A (p.Arg442His)

HGVS:

NC_000005.10:g.151822698C>T
NG_011764.1:g.107139G>A
NM_000171.4:c.1325G>AMANE SELECT
NM_001146040.2:c.1349G>A
NM_001292000.2:c.1076G>A
NP_000162.2:p.Arg442His
NP_001139512.1:p.Arg450His
NP_001278929.1:p.Arg359His
NC_000005.9:g.151202259C>T
NM_000171.3:c.1325G>A

Protein change:

R359H

Links:

dbSNP: rs200130685

NCBI 1000 Genomes Browser:

rs200130685

Molecular consequence:

NM_000171.4:c.1325G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001146040.2:c.1349G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001292000.2:c.1076G>A - 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
SCV000761324	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 18, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24108130, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000761324

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 18, 2023)

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

New hyperekplexia mutations provide insight into glycine receptor assembly, trafficking, and activation mechanisms.

Bode A, Wood SE, Mullins JGL, Keramidas A, Cushion TD, Thomas RH, Pickrell WO, Drew CJG, Masri A, Jones EA, Vassallo G, Born AP, Alehan F, Aharoni S, Bannasch G, Bartsch M, Kara B, Krause A, Karam EG, Matta S, Jain V, Mandel H, et al.

J Biol Chem. 2013 Nov 22;288(47):33745-33759. doi: 10.1074/jbc.M113.509240. Epub 2013 Oct 9.

PubMed [citation]

PMID:: 24108130
PMCID:: PMC3837119

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000761324.8

#	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 arginine, which is basic and polar, with histidine, which is basic and polar, at codon 442 of the GLRA1 protein (p.Arg442His). This variant is present in population databases (rs200130685, gnomAD 0.06%). This missense change has been observed in individual(s) with hyperplexia (PMID: 24108130). This variant is also known as Arg414His. ClinVar contains an entry for this variant (Variation ID: 532834). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLRA1 protein function. Experimental studies have shown that this missense change does not substantially affect GLRA1 function (PMID: 24108130). 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: Mar 5, 2024

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