VCV000224815.4 - ClinVar

NM_007327.4(GRIN1):c.679G>C (p.Asp227His)

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.

(3)

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.

Likely 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_007327.4(GRIN1):c.679G>C (p.Asp227His)

Variation ID: 224815 Accession: VCV000224815.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q34.3 9: 137156676 (GRCh38) [ NCBI UCSC ] 9: 140051128 (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	Apr 3, 2016	Apr 2, 2022	Apr 5, 2016

HGVS

Nucleotide	Protein	Molecular consequence
NM_007327.4:c.679G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_015566.1:p.Asp227His	missense
NM_000832.7:c.679G>C	NP_000823.4:p.Asp227His	missense
NM_001185090.2:c.742G>C	NP_001172019.1:p.Asp248His	missense
NM_001185091.2:c.742G>C	NP_001172020.1:p.Asp248His	missense
NM_021569.4:c.679G>C	NP_067544.1:p.Asp227His	missense
NC_000009.12:g.137156676G>C
NC_000009.11:g.140051128G>C
NG_011507.1:g.22520G>C

... more HGVS ... less HGVS

Protein change

D227H, D248H

Other names

Canonical SPDI

NC_000009.12:137156675:G:C

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

OMIM: 138249.0010 ClinGen: CA357904 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.
GRIN1		-	-	GRCh38 GRCh37	1038	1138

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.
Intellectual disability, autosomal dominant 8	Likely pathogenic (1)	criteria provided, single submitter	Sep 9, 2015	RCV000210389.9
Intellectual disability, autosomal dominant 8 Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive	Likely pathogenic (1)	criteria provided, single submitter	Apr 5, 2016	RCV000760222.10
NEURODEVELOPMENTAL DISORDER WITH HYPERKINETIC MOVEMENTS WITH OR WITHOUT SEIZURES, AUTOSOMAL RECESSIVE	Pathogenic (1)	no assertion criteria provided	Mar 28, 2022	RCV002051695.9

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 pathogenic (Apr 05, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 8 Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV000890052.1 First in ClinVar: Mar 19, 2019 Last updated: Mar 19, 2019
Likely pathogenic (Sep 09, 2015)	criteria provided, single submitter (Bosch et al. (EJHG 2015)) Method: research	Intellectual disability, autosomal dominant 8 Affected status: no, yes Allele origin: germline	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine Accession: SCV000258441.1 First in ClinVar: Apr 03, 2016 Last updated: Apr 03, 2016	Publications: PubMed (1) PubMed: 26350515 Comment: This study shows that diverse genetic causes underlie CVI. Observation 1: Number of individuals with the variant: 1 Age: 0-9 years Sex: female Observation 2: Number of individuals with the variant: 2
Pathogenic (Mar 28, 2022)	no assertion criteria provided Method: literature only	NEURODEVELOPMENTAL DISORDER WITH HYPERKINETIC MOVEMENTS WITH OR WITHOUT SEIZURES, AUTOSOMAL RECESSIVE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000678282.3 First in ClinVar: Jan 13, 2018 Last updated: Apr 02, 2022	Publications: PubMed (2) PubMed: 28051072‚ 27164704 Comment on evidence: In 2 sibs, born of consanguineous Moroccan parents, with autosomal recessive neurodevelopmental disorder with hyperkinetic movements with or without seizures (NDHMSR; 617820), Rossi et al. … (more) In 2 sibs, born of consanguineous Moroccan parents, with autosomal recessive neurodevelopmental disorder with hyperkinetic movements with or without seizures (NDHMSR; 617820), Rossi et al. (2017) identified a homozygous c.679G-C transversion (c.679G-C, NM_007327.3) in the GRIN1 gene, resulting in an asp227-to-his (D227H) substitution at a conserved residue in the zinc-binding site within the amino-terminal domain. The mutation, which was found by massive parallel sequencing of a gene panel and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not found in the Exome Variant Server, 1000 Genomes Project, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed, but Rossi et al. (2017) hypothesized that missense variants in the amino-terminal domain of the protein may be hypomorphic and pathogenic in the homozygous state, whereas the functionality of 1 allele, as observed in the parents, is sufficient to avoid clinical expression in heterozygous carriers. Another homozygous missense mutation in the amino-terminal domain (R217W; 138249.0008) was identified in 2 brothers with a similar intellectual disability phenotype without seizures (Lemke et al., 2016). (less)

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Novel homozygous missense variant of GRIN1 in two sibs with intellectual disability and autistic features without epilepsy.	Rossi M	European journal of human genetics : EJHG	2017	PMID: 28051072
Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy.	Lemke JR	Neurology	2016	PMID: 27164704

Text-mined citations for this variant ...

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_007327.4(GRIN1):c.679G>C (p.Asp227His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...