ClinVar Genomic variation as it relates to human health
NM_022455.5(NSD1):c.5951G>A (p.Arg1984Gln)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_022455.5(NSD1):c.5951G>A (p.Arg1984Gln)
Variation ID: 159390 Accession: VCV000159390.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q35.3 5: 177282523 (GRCh38) [ NCBI UCSC ] 5: 176709524 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Nov 23, 2014 Jul 15, 2024 Apr 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_022455.5:c.5951G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_071900.2:p.Arg1984Gln missense NM_001365684.2:c.5078G>A NP_001352613.2:p.Arg1693Gln missense NM_001409301.1:c.5951G>A NP_001396230.1:p.Arg1984Gln missense NM_001409302.1:c.5951G>A NP_001396231.1:p.Arg1984Gln missense NM_001409303.1:c.5951G>A NP_001396232.1:p.Arg1984Gln missense NM_001409304.1:c.5531G>A NP_001396233.1:p.Arg1844Gln missense NM_001409305.1:c.5198G>A NP_001396234.1:p.Arg1733Gln missense NM_001409306.1:c.5189G>A NP_001396235.1:p.Arg1730Gln missense NM_001409307.1:c.5189G>A NP_001396236.1:p.Arg1730Gln missense NM_001409308.1:c.5078G>A NP_001396237.1:p.Arg1693Gln missense NM_001409309.1:c.5078G>A NP_001396238.1:p.Arg1693Gln missense NM_172349.5:c.5078G>A NP_758859.2:p.Arg1693Gln missense NC_000005.10:g.177282523G>A NC_000005.9:g.176709524G>A NG_009821.1:g.154445G>A LRG_512:g.154445G>A LRG_512t1:c.5951G>A LRG_512p1:p.Arg1984Gln Q96L73:p.Arg1984Gln - Protein change
- R1984Q, R1715Q, R1693Q, R1730Q, R1733Q, R1844Q
- Other names
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- Canonical SPDI
- NC_000005.10:177282522:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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NSD1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1734 | 1849 |
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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Dec 13, 2021 | RCV000405920.12 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 19, 2024 | RCV003231289.10 |
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
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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. |
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Pathogenic
(Dec 13, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329440.7
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21196496, 17565729, 24412544, 27834868, 16010675, 17561922, 15452385, 16247291, 12807965, 29142766) (less)
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Pathogenic
(Feb 08, 2013)
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criteria provided, single submitter
Method: clinical testing
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Sotos syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000194227.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Pathogenic
(Jul 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Sotos syndrome
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002054958.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
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Pathogenic
(Apr 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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None
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001585359.3
First in ClinVar: May 10, 2021 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1984 of the NSD1 protein (p.Arg1984Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1984 of the NSD1 protein (p.Arg1984Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Sotos syndrome (PMID: 12807965, 15942875, 16247291, 17561922, 17565729). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 159390). 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 NSD1 protein function. Experimental studies have shown that this missense change affects NSD1 function (PMID: 21196496, 24412544, 27834868). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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Sotos syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005077162.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 |
Comment:
Variant summary: NSD1 c.5951G>A (p.Arg1984Gln) results in a conservative amino acid change located in the SET domain (IPR001214) of the encoded protein sequence. Four of … (more)
Variant summary: NSD1 c.5951G>A (p.Arg1984Gln) results in a conservative amino acid change located in the SET domain (IPR001214) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251304 control chromosomes (gnomAD). c.5951G>A has been reported in the literature in individuals affected with Sotos Syndrome, including one de novo occurrence (Tatton-Brown_2005, Lu_2017). These data indicate that the variant is likely to be associated with disease. At least two publication report experimental evidence evaluating an impact on protein function and this variant results in completely lost its ability to methylate H3 (Qiao_2010, Kudithipudi_2014). The following publications have been ascertained in the context of this evaluation (PMID: 27834868, 24412544, 29142766, 21196496, 15942875). ClinVar contains an entry for this variant (Variation ID: 159390). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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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
HelpTitle | Author | Journal | Year | Link |
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Mutations in NSD1 and NFIX in Three Patients with Clinical Features of Sotos Syndrome and Malan Syndrome. | Lu Y | Journal of pediatric genetics | 2017 | PMID: 29142766 |
Steric Clash in the SET Domain of Histone Methyltransferase NSD1 as a Cause of Sotos Syndrome and Its Genetic Heterogeneity in a Brazilian Cohort. | Ha K | Genes | 2016 | PMID: 27834868 |
Substrate specificity analysis and novel substrates of the protein lysine methyltransferase NSD1. | Kudithipudi S | Chemistry & biology | 2014 | PMID: 24412544 |
The structure of NSD1 reveals an autoregulatory mechanism underlying histone H3K36 methylation. | Qiao Q | The Journal of biological chemistry | 2011 | PMID: 21196496 |
Heterogeneity of NSD1 alterations in 116 patients with Sotos syndrome. | Saugier-Veber P | Human mutation | 2007 | PMID: 17565729 |
Leukocyte cDNA analysis of NSD1 derived from confirmed Sotos syndrome patients. | Duno M | Annals of human genetics | 2007 | PMID: 17561922 |
NSD1 analysis for Sotos syndrome: insights and perspectives from the clinical laboratory. | Waggoner DJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2005 | PMID: 16247291 |
Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. | Tatton-Brown K | American journal of human genetics | 2005 | PMID: 15942875 |
Spectrum of NSD1 mutations in Sotos and Weaver syndromes. | Rio M | Journal of medical genetics | 2003 | PMID: 12807965 |
Text-mined citations for rs587784169 ...
HelpRecord last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.