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NM_007327.4(GRIN1):c.1979C>T (p.Pro660Leu) AND Intellectual disability, autosomal dominant 8

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jul 12, 2022
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV001004900.7

Allele description [Variation Report for NM_007327.4(GRIN1):c.1979C>T (p.Pro660Leu)]

NM_007327.4(GRIN1):c.1979C>T (p.Pro660Leu)

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.1979C>T (p.Pro660Leu)
HGVS:
  • NC_000009.12:g.137162705C>T
  • NG_011507.1:g.28549C>T
  • NM_000832.7:c.1979C>T
  • NM_001185090.2:c.2042C>T
  • NM_001185091.2:c.2042C>T
  • NM_007327.4:c.1979C>TMANE SELECT
  • NM_021569.4:c.1979C>T
  • NP_000823.4:p.Pro660Leu
  • NP_001172019.1:p.Pro681Leu
  • NP_001172020.1:p.Pro681Leu
  • NP_015566.1:p.Pro660Leu
  • NP_067544.1:p.Pro660Leu
  • NC_000009.11:g.140057157C>T
  • NC_000009.11:g.140057157C>T
  • NM_007327.3:c.1979C>T
  • p.Pro681Leu
Protein change:
P660L
Links:
dbSNP: rs1328780843
NCBI 1000 Genomes Browser:
rs1328780843
Molecular consequence:
  • NM_000832.7:c.1979C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001185090.2:c.2042C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001185091.2:c.2042C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007327.4:c.1979C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_021569.4:c.1979C>T - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001164397Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Dec 3, 2018)
germlineresearch

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

SCV002194180Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Jul 12, 2022)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedresearch
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001164397.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)

Description

The heterozygous p.Pro681Leu variant in GRIN1 was identified by our study in one individual with mental retardation. This variant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The GRIN1 gene has a low rate of benign missense variation, raising the possibility that a missense variant would not be tolerated in this gene. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP2 (Richards 2015).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV002194180.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant has not been reported in the literature in individuals affected with GRIN1-related conditions. 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) performed at Invitae indicates that this missense variant is expected to disrupt GRIN1 protein function. ClinVar contains an entry for this variant (Variation ID: 813929). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 660 of the GRIN1 protein (p.Pro660Leu).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 23, 2024