ClinVar Genomic variation as it relates to human health
NM_022455.5(NSD1):c.6050G>A (p.Arg2017Gln)
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.6050G>A (p.Arg2017Gln)
Variation ID: 159398 Accession: VCV000159398.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q35.3 5: 177283827 (GRCh38) [ NCBI UCSC ] 5: 176710828 (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 Mar 4, 2023 Sep 2, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_022455.5:c.6050G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_071900.2:p.Arg2017Gln missense NM_001365684.2:c.5177G>A NP_001352613.2:p.Arg1726Gln missense NM_001409301.1:c.6050G>A NP_001396230.1:p.Arg2017Gln missense NM_001409302.1:c.6050G>A NP_001396231.1:p.Arg2017Gln missense NM_001409303.1:c.6050G>A NP_001396232.1:p.Arg2017Gln missense NM_001409304.1:c.5630G>A NP_001396233.1:p.Arg1877Gln missense NM_001409305.1:c.5297G>A NP_001396234.1:p.Arg1766Gln missense NM_001409306.1:c.5288G>A NP_001396235.1:p.Arg1763Gln missense NM_001409307.1:c.5288G>A NP_001396236.1:p.Arg1763Gln missense NM_001409308.1:c.5177G>A NP_001396237.1:p.Arg1726Gln missense NM_172349.5:c.5177G>A NP_758859.2:p.Arg1726Gln missense NC_000005.10:g.177283827G>A NC_000005.9:g.176710828G>A NG_009821.1:g.155749G>A LRG_512:g.155749G>A LRG_512t1:c.6050G>A LRG_512p1:p.Arg2017Gln Q96L73:p.Arg2017Gln - Protein change
- R2017Q, R1748Q, R1763Q, R1877Q, R1726Q, R1766Q
- Other names
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- Canonical SPDI
- NC_000005.10:177283826: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
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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
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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 |
1678 | 1791 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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May 14, 2014 | RCV000415049.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 13, 2013 | RCV000414978.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 11, 2020 | RCV000290468.11 | |
Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Sep 2, 2022 | RCV003231297.8 |
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. |
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Pathogenic
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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None
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782188.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Sotos syndrome
Affected status: yes
Allele origin:
unknown
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Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn
Accession: SCV000999348.1
First in ClinVar: Nov 29, 2019 Last updated: Nov 29, 2019 |
Number of individuals with the variant: 1
Clinical Features:
High forehead (present) , Broad-based gait (present) , Behavioral abnormality (present) , Increased body weight (present) , Tall stature (present) , Osteopenia (present) , Overgrowth … (more)
High forehead (present) , Broad-based gait (present) , Behavioral abnormality (present) , Increased body weight (present) , Tall stature (present) , Osteopenia (present) , Overgrowth (present) , Pointed chin (present) , Recurrent otitis media (present) , Sparse anterior scalp hair (present) , Macrocephalus (present) (less)
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Pathogenic
(May 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Sotos syndrome
Affected status: yes
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV002577602.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
PM1, PM2, PM5, PP2, PP3, PP5
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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: SCV000194235.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Likely pathogenic
(May 14, 2014)
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criteria provided, single submitter
Method: clinical testing
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Delayed gross motor development
Delayed speech and language development Global developmental delay High anterior hairline Hypertelorism Hypoplasia of the corpus callosum Scoliosis
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000493005.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
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Likely pathogenic
(Dec 13, 2013)
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criteria provided, single submitter
Method: clinical testing
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Delayed speech and language development
High forehead Increased body weight Macrocephaly Osteopenia Overgrowth Pointed chin Preeclampsia Tall stature
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000493045.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
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Likely pathogenic
(Jan 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Sotos syndrome
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367283.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Likely pathogenic.
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Likely 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: SCV002054964.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
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Pathogenic
(Sep 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Sotos syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767016.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Sotos syndrome (MIM#117550). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated SET domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals, some of which are reported de novo events, and is consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMIDs:12464997, 27834868, 30719864). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Aug 26, 2021)
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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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Invitae
Accession: SCV002136600.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine with glutamine at codon 2017 of the NSD1 protein (p.Arg2017Gln). The arginine residue is highly conserved and there is a … (more)
This sequence change replaces arginine with glutamine at codon 2017 of the NSD1 protein (p.Arg2017Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Sotos syndrome (PMID: 17565729, 27834868). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 159398). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects NSD1 function (PMID: 21196496). This variant disrupts the p.Arg2017 amino acid residue in NSD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12807965, 15942875, 24412544, 26690673). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 11, 2020)
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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: SCV000329438.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Identified in multiple patients with Sotos Syndrome (Douglas et al., 2003; Tatton-Brown et al., 2005; Saugier-Veber et al., 2007; Kotilainen et al., 2009; Ha et … (more)
Identified in multiple patients with Sotos Syndrome (Douglas et al., 2003; Tatton-Brown et al., 2005; Saugier-Veber et al., 2007; Kotilainen et al., 2009; Ha et al., 2016); Published functional studies demonstrate a damaging effect on the histone methyltransferase (HMT) activity (Qiao et al., 2011); 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: 16010675, 17565729, 12464997, 21196496, 15942875, 19876911, 27834868, 30719864) (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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Hyperinsulinemic hypoglycemia in seven patients with de novo NSD1 mutations. | Grand K | American journal of medical genetics. Part A | 2019 | PMID: 30719864 |
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 |
NSD1 mutations generate a genome-wide DNA methylation signature. | Choufani S | Nature communications | 2015 | PMID: 26690673 |
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 |
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 |
NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes. | Douglas J | American journal of human genetics | 2003 | PMID: 12464997 |
Text-mined citations for rs587784177 ...
HelpRecord last updated Jun 10, 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.