NM_007327.4(GRIN1):c.421G>A (p.Val141Met) AND Intellectual disability, autosomal dominant 8

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Feb 8, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001067257.13

Allele description [Variation Report for NM_007327.4(GRIN1):c.421G>A (p.Val141Met)]

NM_007327.4(GRIN1):c.421G>A (p.Val141Met)

Gene:

GRIN1:glutamate ionotropic receptor NMDA type subunit 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.3

Genomic location:

Preferred name:

NM_007327.4(GRIN1):c.421G>A (p.Val141Met)

HGVS:

NC_000009.12:g.137145753G>A
NG_011507.1:g.11597G>A
NM_000832.7:c.421G>A
NM_001185090.2:c.421G>A
NM_001185091.2:c.421G>A
NM_007327.4:c.421G>AMANE SELECT
NM_021569.4:c.421G>A
NP_000823.4:p.Val141Met
NP_001172019.1:p.Val141Met
NP_001172020.1:p.Val141Met
NP_015566.1:p.Val141Met
NP_067544.1:p.Val141Met
NC_000009.11:g.140040205G>A
NC_000009.11:g.140040205G>A
NM_007327.3:c.421G>A

Protein change:

V141M

Links:

dbSNP: rs1293947350

NCBI 1000 Genomes Browser:

rs1293947350

Molecular consequence:

NM_000832.7:c.421G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001185090.2:c.421G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001185091.2:c.421G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_007327.4:c.421G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_021569.4:c.421G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Intellectual disability, autosomal dominant 8 (NDHMSD)
Synonyms:: Mental retardation, autosomal dominant 8; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant
Identifiers:: MONDO: MONDO:0013655; MedGen: C3280282; OMIM: 614254

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001232307	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 8, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002760093	Laboratory of Medical Genetics, University of Torino - NeuroWES	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 29, 2022)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV003921962	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 19, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23454977, 27164704, 29365063, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001232307

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 8, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002760093

Laboratory of Medical Genetics, University of Torino - NeuroWES

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 29, 2022)

germline

research

PubMed (1)
[See all records that cite this PMID]

SCV003921962

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 19, 2020)

germline

clinical testing

PubMed (4)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Allosteric signaling and dynamics of the clamshell-like NMDA receptor GluN1 N-terminal domain.

Zhu S, Stroebel D, Yao CA, Taly A, Paoletti P.

Nat Struct Mol Biol. 2013 Apr;20(4):477-85. doi: 10.1038/nsmb.2522. Epub 2013 Mar 3.

PubMed [citation]

PMID:: 23454977

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001232307.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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. 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 GRIN1 protein function. ClinVar contains an entry for this variant (Variation ID: 860867). This variant has not been reported in the literature in individuals affected with GRIN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 141 of the GRIN1 protein (p.Val141Met).

#	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

From Laboratory of Medical Genetics, University of Torino - NeuroWES, SCV002760093.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV003921962.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as likely pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene and are associated with both autosomal dominant and recessive neurodevelopmental disorder with or without hyperkinetic movements and seizures (MIM#614254, MIM#617820). (I) 0108 - This gene is associated with both recessive and dominant disease. Missense variants and variants predicted to result in a premature termination codon located in the N-terminal domain, tend to be associated to recessive disease. Missense mutations with both gain of function and dominant negative consequences on protein function are associated to dominant disease, and tend to be found in C-terminal domains (PMID: 27164704, PMID: 29365063, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0601 - Variant is located in the well-established functional hinge region of the N-terminal domain. Seven alternative missense changes at this residue have been functionally proven to have both loss and gain of function effects in channel activity (PMID: 23454977). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 25, 2025

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