NM_000171.4(GLRA1):c.523A>G (p.Met175Val) AND Hereditary hyperekplexia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 30, 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:: RCV001328517.7

Allele description [Variation Report for NM_000171.4(GLRA1):c.523A>G (p.Met175Val)]

NM_000171.4(GLRA1):c.523A>G (p.Met175Val)

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.523A>G (p.Met175Val)

Other names:

M147V

HGVS:

NC_000005.10:g.151856337T>C
NG_011764.1:g.73500A>G
NM_000171.4:c.523A>GMANE SELECT
NM_001146040.2:c.523A>G
NM_001292000.2:c.274A>G
NP_000162.2:p.Met175Val
NP_001139512.1:p.Met175Val
NP_001278929.1:p.Met92Val
NC_000005.9:g.151235898T>C
NM_000171.3:c.523A>G

Protein change:

M175V; MET147VAL

Links:

OMIM: 138491.0009; dbSNP: rs121918414

NCBI 1000 Genomes Browser:

rs121918414

Molecular consequence:

NM_000171.4:c.523A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001146040.2:c.523A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001292000.2:c.274A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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STAT4KO_HNEG_D0_001
STAT4KO_HNEG_D0_001

GEO DataSets
D2045.8 BTB domain-containing protein [Caenorhabditis elegans]
D2045.8 BTB domain-containing protein [Caenorhabditis elegans]
Gene ID:176468

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001223698	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11702206, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001223698

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 30, 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

Compound heterozygosity and nonsense mutations in the alpha(1)-subunit of the inhibitory glycine receptor in hyperekplexia.

Rees MI, Lewis TM, Vafa B, Ferrie C, Corry P, Muntoni F, Jungbluth H, Stephenson JB, Kerr M, Snell RG, Schofield PR, Owen MJ.

Hum Genet. 2001 Sep;109(3):267-70.

PubMed [citation]

PMID:: 11702206

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001223698.5

#	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 methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 175 of the GLRA1 protein (p.Met175Val). This variant is present in population databases (rs121918414, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive hyperekplexia (PMID: 11702206). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as M147V (A830G). ClinVar contains an entry for this variant (Variation ID: 16068). 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%. Experimental studies have shown that this missense change does not substantially affect GLRA1 function (PMID: 11702206). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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: Sep 29, 2024

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