VCV000038327.26 - ClinVar

NM_000171.4(GLRA1):c.1108G>A (p.Gly370Ser)

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.

(12)

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.

Benign/Likely benign

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.1108G>A (p.Gly370Ser)

Variation ID: 38327 Accession: VCV000038327.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q33.1 5: 151822915 (GRCh38) [ NCBI UCSC ] 5: 151202476 (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	Oct 8, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000171.4:c.1108G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000162.2:p.Gly370Ser	missense
NM_001146040.2:c.1132G>A	NP_001139512.1:p.Gly378Ser	missense
NM_001292000.2:c.859G>A	NP_001278929.1:p.Gly287Ser	missense
NC_000005.10:g.151822915C>T
NC_000005.9:g.151202476C>T
NG_011764.1:g.106922G>A

... more HGVS ... less HGVS

Protein change

G378S, G370S, G287S

Other names

G1406A

Canonical SPDI

NC_000005.10:151822914: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.

0.00379 (T)

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

The Genome Aggregation Database (gnomAD), exomes 0.00962

Exome Aggregation Consortium (ExAC) 0.01004

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01130

1000 Genomes Project 30x 0.00344

1000 Genomes Project 0.00379

Trans-Omics for Precision Medicine (TOPMed) 0.00922

The Genome Aggregation Database (gnomAD) 0.00939

Links

ClinGen: CA342947 dbSNP: rs116474260 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	Benign/Likely benign (7)	criteria provided, multiple submitters, no conflicts	May 4, 2023	RCV000031885.22
not specified	Likely benign (1)	criteria provided, single submitter	Mar 28, 2016	RCV000454994.5
Hereditary hyperekplexia	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV001507199.8
not provided	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Oct 22, 2019	RCV001705618.2
GLRA1-related disorder	Benign (1)	no assertion criteria provided	Mar 5, 2019	RCV003924880.2

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.
Likely benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Hyperekplexia 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001137013.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hyperekplexia 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000455424.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (4) PubMed: 11702206‚ 25333069‚ 10817489‚ 20631190 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Feb 01, 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: SCV000638477.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024
Likely benign (Mar 28, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000539244.1 First in ClinVar: Apr 09, 2017 Last updated: Apr 09, 2017	Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: DM? in HGMD, frequency (less) Method: Genome/Exome Filtration
Benign (Oct 09, 2014)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Hyperekplexia 1 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743539.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hyperekplexia 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001435247.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Comment: The heterozygous p.Gly370Ser variant, sometimes called p.Gly342Ser or p.Gly378Ser due to a difference in cDNA numbering, in GLRA1 has been identified in an individual with … (more) The heterozygous p.Gly370Ser variant, sometimes called p.Gly342Ser or p.Gly378Ser due to a difference in cDNA numbering, in GLRA1 has been identified in an individual with hyperekplexia and their unaffected parent (PMID: 10817489). This variant has also been identified in >1% of European (non-Finnish) chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Gly370Ser variant may not impact protein function (PMID: 10817489). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for hyperekplexia. (less)
Benign (Oct 22, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001900661.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Comment: This variant is associated with the following publications: (PMID: 27535533, 26764160, 27884173, 10817489, 20981092, 25333069, 20631190)
Benign (May 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hyperekplexia 1 Affected status: yes Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002503663.2 First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024	Comment: European Non-Finnish population allele frequency is 1.473% (rs116474260, 1959/128696 alleles, 15 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, … (more) European Non-Finnish population allele frequency is 1.473% (rs116474260, 1959/128696 alleles, 15 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 (less)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005226613.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	Hyperekplexia 1 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000734388.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (Mar 05, 2019)	no assertion criteria provided Method: clinical testing	GLRA1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004739185.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
pathologic (Oct 04, 2012)	Flagged submission flagged submission Method: curation Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Hyperekplexia Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000054499.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2013	Comment: Converted during submission to Pathogenic.
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: DM? in HGMD, frequency

Comment:

The heterozygous p.Gly370Ser variant, sometimes called p.Gly342Ser or p.Gly378Ser due to a difference in cDNA numbering, in GLRA1 has been identified in an individual with hyperekplexia and their unaffected parent (PMID: 10817489). This variant has also been identified in >1% of European (non-Finnish) chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Gly370Ser variant may not impact protein function (PMID: 10817489). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for hyperekplexia.

Comment:

European Non-Finnish population allele frequency is 1.473% (rs116474260, 1959/128696 alleles, 15 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1

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
Hereditary Hyperekplexia Overview.	Adam MP	-	2019	PMID: 20301437
Disease variants in genomes of 44 centenarians.	Freudenberg-Hua Y	Molecular genetics & genomic medicine	2014	PMID: 25333069
Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia.	Chung SK	The Journal of neuroscience : the official journal of the Society for Neuroscience	2010	PMID: 20631190
Compound heterozygosity and nonsense mutations in the alpha(1)-subunit of the inhibitory glycine receptor in hyperekplexia.	Rees MI	Human genetics	2001	PMID: 11702206
An unusual case of hyperekplexia.	Jungbluth H	European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society	2000	PMID: 10817489

Text-mined citations for rs116474260 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000171.4(GLRA1):c.1108G>A (p.Gly370Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs116474260 ...