VCV000016061.16 - ClinVar

NM_000171.4(GLRA1):c.896G>A (p.Arg299Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(9)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000171.4(GLRA1):c.896G>A (p.Arg299Gln)

Variation ID: 16061 Accession: VCV000016061.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q33.1 5: 151851406 (GRCh38) [ NCBI UCSC ] 5: 151230967 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 1, 2013	Nov 24, 2024	Jan 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000171.4:c.896G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000162.2:p.Arg299Gln	missense
NM_001146040.2:c.896G>A	NP_001139512.1:p.Arg299Gln	missense
NM_001292000.2:c.647G>A	NP_001278929.1:p.Arg216Gln	missense
NC_000005.10:g.151851406C>T
NC_000005.9:g.151230967C>T
NG_011764.1:g.78431G>A
	P23415:p.Arg299Gln

... more HGVS ... less HGVS

Protein change

R299Q, R216Q

Other names

R271Q
G1192A

Canonical SPDI

NC_000005.10:151851405:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA341359 UniProtKB: P23415#VAR_000299 OMIM: 138491.0002 dbSNP: rs121918408 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GLRA1		-	-	GRCh38 GRCh37	500	517

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hyperekplexia 1	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Aug 24, 2023	RCV000017439.38
Sleep myoclonus	Pathogenic (1)	criteria provided, single submitter	Jan 7, 2020	RCV001256113.3
not provided	Pathogenic (1)	criteria provided, single submitter	Jan 24, 2022	RCV001818164.4
Hereditary hyperekplexia	Pathogenic (1)	criteria provided, single submitter	Jan 7, 2024	RCV001376594.7

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 24, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002064163.2 First in ClinVar: Jan 29, 2022 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate this variant impairs chloride channel activation and conductance (Langosch et al., 1994; Moraga-Cid et al., 2015); Not observed at significant frequency … (more) Published functional studies demonstrate this variant impairs chloride channel activation and conductance (Langosch et al., 1994; Moraga-Cid et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9009272, 7881416, 1355335, 1897565, 6830476, 7826634, 7925268, 30109271, 25730860, 8298642, 28122427) (less)
Pathogenic (Jan 07, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary hyperekplexia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000638498.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (7) PubMed: 28492532‚ 8298642‚ 8733061‚ 28122427‚ 28138086‚ 7518444‚ 7881416 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 299 of the GLRA1 protein (p.Arg299Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 299 of the GLRA1 protein (p.Arg299Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hyperekplexia, also known as startle syndrome (PMID: 8298642, 8733061, 28122427, 28138086). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16061). 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 affects GLRA1 function (PMID: 7518444). This variant disrupts the p.Arg299 amino acid residue in GLRA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7881416, 8298642). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 30, 2016)	criteria provided, single submitter (Submitter's publication) Method: research	HYPEREKPLEXIA, HEREDITARY 1 Affected status: yes Allele origin: germline	ITMI Accession: SCV000538082.2 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017	Publications: PubMed (1) PubMed: 28617419
Pathogenic (Jan 07, 2020)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Sleep myoclonus (Autosomal dominant inheritance) Affected status: yes Allele origin: paternal	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV001432901.1 First in ClinVar: Sep 24, 2020 Last updated: Sep 24, 2020	Publications: PubMed (4) PubMed: 8298642‚ 8733061‚ 28138086‚ 7881416 Comment: The p.Arg299Gln variant (also known as p.Arg271Gln) identified in this individual has been reported in multiple patients affected with autosomal dominant hyperekplexia/startle syndrome, and co-segregates … (more) The p.Arg299Gln variant (also known as p.Arg271Gln) identified in this individual has been reported in multiple patients affected with autosomal dominant hyperekplexia/startle syndrome, and co-segregates with autosomal dominant hyperekplexia in several families [PMID: 8298642; PMID: 8733061; PMID: 28138086]. The variant is absent from the gnomAD database indicating it is an extremely rare allele in the general population. The variant affects a highly conserved residue and is predicted deleterious by in silico tools. Functional studies have found that the mutant allele results in reduced glycinergic inhibitory neurotransmission by the glycine receptor-channel complex [PMID: 7518444]. Moreover, a different missense variant affecting the same Arg299 of GLRA1 has also been reported in several affected individuals [PMID: 8298642; PMID: 7881416].Based on the available evidence, the p.Arg299Gln variant in the GLRA1 gene is assessed as pathogenic. (less) Secondary finding: no
Pathogenic (Oct 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hyperekplexia 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002761475.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Pathogenic (Aug 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hyperekplexia 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440251.3 First in ClinVar: Oct 30, 2020 Last updated: Dec 17, 2023	Comment: Criteria applied: PS2,PS3,PS4,PM5_STR,PM1,PM2_SUP,PP3,PP4 Clinical Features: Hypertonia (present) , Asymmetry of iris pigmentation (present) , Muscle stiffness (present) , Syncope (present) , Kayser-Fleischer ring (present) Sex: female
Pathogenic (May 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hyperekplexia 1 Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005399131.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (7) PubMed: 11389164‚ 14673895‚ 17536053‚ 25356525‚ 28122427‚ 30866851‚ 32319239 Comment: Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hyperekplexia 1 (MIM#149400). Dominant negative has also been suggested for a single variant (PMID: 17536053). (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal recessive (AR) variants are located throughout the gene while autosomal dominant (AD) variants are mostly located within the TM2-Loop2 domains (PMID: 32319239). (I) 0115 - Variants in this gene are known to have variable expressivity. In a single AR family with two affected brothers, one was more severely affected than the other (PMID: 30866851). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants within the pore-forming M2 transmembrane domain (DECIPHER; PMID: 25356525). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as Arg271Gln in the literature, at least ten patients with AD hyperekplexia 1 (MIM#149400) have been reported to harbour this variant (ClinVar, PMID: 11389164, 14673895, 25356525, 28122427). (SP) 0901 - This variant has strong evidence for segregation with disease. It has been shown to segregate in a large 3-generation family with nine affecteds (PMID: 11389164). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (May 01, 1996)	no assertion criteria provided Method: literature only	HYPEREKPLEXIA 1, AUTOSOMAL DOMINANT Affected status: not provided Allele origin: germline	OMIM Accession: SCV000037711.3 First in ClinVar: Apr 04, 2013 Last updated: Aug 19, 2015	Publications: PubMed (7) PubMed: 8298642‚ 1334371‚ 7881416‚ 7981700‚ 7518444‚ 7611730‚ 8733061 Comment on evidence: In affected members of 3 families with hyperekplexia-1 (HKPX1; 149400), Shiang et al. (1993) identified a heterozygous 1192G-A transition in exon 6 of the GLRA1 … (more) In affected members of 3 families with hyperekplexia-1 (HKPX1; 149400), Shiang et al. (1993) identified a heterozygous 1192G-A transition in exon 6 of the GLRA1 gene, resulting in an arg271-to-gln (R271Q) substitution in the extracellular domain adjacent to the second transmembrane domain. One of the families had previously been reported by Ryan et al. (1992). Rees et al. (1994) demonstrated the R271Q mutation in affected members of a U.K. family showing autosomal dominant transmission of startle disease. In a 17-year-old Swiss girl who had had numerous episodes of falling and myoclonia in response to stimuli, Schorderet et al. (1994) identified a heterozygous 1192G-A mutation in the GLRA1 gene. Her older sister and mother also suffered from abnormal startle reflex. Rajendra et al. (1994) demonstrated that the R271Q mutation causes a significant decrease in the binding affinity for glycine and a decrease in the sensitivity of receptor currents activated by glycine, thus reducing glycinergic inhibitory neurotransmission by producing receptors with diminished agonist responsiveness. Shiang et al. (1995) reported an additional 5 hyperekplexia families with the 1192G-A mutation. Haplotype analysis suggested that this mutation has arisen at least twice and possibly 4 times. Elmslie et al. (1996) found the R271Q mutation in 2 of 8 probands with familial hyperekplexia. (less)
pathologic (Oct 04, 2012)	no assertion criteria provided Method: curation	Hyperekplexia Affected status: not provided Allele origin: not provided	GeneReviews Accession: SCV000054510.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2013	Comment: Converted during submission to Pathogenic.

Comment:

Published functional studies demonstrate this variant impairs chloride channel activation and conductance (Langosch et al., 1994; Moraga-Cid et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9009272, 7881416, 1355335, 1897565, 6830476, 7826634, 7925268, 30109271, 25730860, 8298642, 28122427)

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 299 of the GLRA1 protein (p.Arg299Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hyperekplexia, also known as startle syndrome (PMID: 8298642, 8733061, 28122427, 28138086). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16061). 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 affects GLRA1 function (PMID: 7518444). This variant disrupts the p.Arg299 amino acid residue in GLRA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7881416, 8298642). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Arg299Gln variant (also known as p.Arg271Gln) identified in this individual has been reported in multiple patients affected with autosomal dominant hyperekplexia/startle syndrome, and co-segregates with autosomal dominant hyperekplexia in several families [PMID: 8298642; PMID: 8733061; PMID: 28138086]. The variant is absent from the gnomAD database indicating it is an extremely rare allele in the general population. The variant affects a highly conserved residue and is predicted deleterious by in silico tools. Functional studies have found that the mutant allele results in reduced glycinergic inhibitory neurotransmission by the glycine receptor-channel complex [PMID: 7518444]. Moreover, a different missense variant affecting the same Arg299 of GLRA1 has also been reported in several affected individuals [PMID: 8298642; PMID: 7881416].Based on the available evidence, the p.Arg299Gln variant in the GLRA1 gene is assessed as pathogenic.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hyperekplexia 1 (MIM#149400). Dominant negative has also been suggested for a single variant (PMID: 17536053). (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal recessive (AR) variants are located throughout the gene while autosomal dominant (AD) variants are mostly located within the TM2-Loop2 domains (PMID: 32319239). (I) 0115 - Variants in this gene are known to have variable expressivity. In a single AR family with two affected brothers, one was more severely affected than the other (PMID: 30866851). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants within the pore-forming M2 transmembrane domain (DECIPHER; PMID: 25356525). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as Arg271Gln in the literature, at least ten patients with AD hyperekplexia 1 (MIM#149400) have been reported to harbour this variant (ClinVar, PMID: 11389164, 14673895, 25356525, 28122427). (SP) 0901 - This variant has strong evidence for segregation with disease. It has been shown to segregate in a large 3-generation family with nine affecteds (PMID: 11389164). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Excessive Startle with Novel GLRA1 Mutations in 4 Chinese Patients and a Literature Review of GLRA1-Related Hyperekplexia.	Zhan F	Journal of clinical neurology (Seoul, Korea)	2020	PMID: 32319239
Clinical features and genetic analysis of two siblings with startle disease in an Italian family: a case report.	Sprovieri T	BMC medical genetics	2019	PMID: 30866851
Hereditary Hyperekplexia Overview.	Adam MP	-	2019	PMID: 20301437
Utilization of genomic sequencing for population screening of immunodeficiencies in the newborn.	Pavey AR	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 28617419
Clinical Reasoning: A 35-year-old woman with hyperstartling, stiffness, and accidental falls: A startling diagnosis.	Russo SP	Neurology	2017	PMID: 28138086
Familial Hyperekplexia, a Potential Cause of Cautious Gait: A New Korean Case and a Systematic Review of Phenotypes.	Lee Y	Journal of movement disorders	2017	PMID: 28122427
Clinical and genetic investigation of 17 Japanese patients with hyperekplexia.	Mine J	Developmental medicine and child neurology	2015	PMID: 25356525
Hyperekplexia caused by dominant-negative suppression of glyra1 function.	Bellini G	Neurology	2007	PMID: 17536053
Magnetic resonance spectroscopy of cerebral cortex is normal in hereditary hyperekplexia due to mutations in the GLRA1 gene.	Tijssen MA	Movement disorders : official journal of the Movement Disorder Society	2003	PMID: 14673895
Mutations in the glycine receptor alpha1 subunit (GLRA1) gene in hereditary hyperekplexia pedigrees: evidence for non-penetrance of mutation Y279C.	Kwok JB	Journal of medical genetics	2001	PMID: 11389164
Analysis of GLRA1 in hereditary and sporadic hyperekplexia: a novel mutation in a family cosegregating for hyperekplexia and spastic paraparesis.	Elmslie FV	Journal of medical genetics	1996	PMID: 8733061
Mutational analysis of familial and sporadic hyperekplexia.	Shiang R	Annals of neurology	1995	PMID: 7611730
An additional family with Startle disease and a G1192A mutation at the alpha 1 subunit of the inhibitory glycine receptor gene.	Schorderet DF	Human molecular genetics	1994	PMID: 7981700
Evidence for recessive as well as dominant forms of startle disease (hyperekplexia) caused by mutations in the alpha 1 subunit of the inhibitory glycine receptor.	Rees MI	Human molecular genetics	1994	PMID: 7881416
Startle disease mutations reduce the agonist sensitivity of the human inhibitory glycine receptor.	Rajendra S	The Journal of biological chemistry	1994	PMID: 7518444
Mutations in the alpha 1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia.	Shiang R	Nature genetics	1993	PMID: 8298642
Genetic and radiation hybrid mapping of the hyperekplexia region on chromosome 5q.	Ryan SG	American journal of human genetics	1992	PMID: 1334371
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Text-mined citations for rs121918408 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000171.4(GLRA1):c.896G>A (p.Arg299Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121918408 ...