The c.3549dup;p.(Glu1184*) is a null frameshift variant in the NSD1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 211726; PMID: 12464997; 15942875; 16247291; 22924495; 28475857) - PS4. This variant is not present in population databases (rs797045813, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.
ClinVar Genomic variation as it relates to human health
NM_022455.5(NSD1):c.3549dup (p.Glu1184Ter)
Germline
Classification
Help
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.
(6)
Help
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.
Pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_022455.5(NSD1):c.3549dup (p.Glu1184Ter)
Variation ID: 211726 Accession: VCV000211726.25
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 5q35.3 5: 177211947-177211948 (GRCh38) [ NCBI UCSC ] 5: 176638948-176638949 (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 Oct 5, 2015 Oct 20, 2024 May 1, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_022455.5:c.3549dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_071900.2:p.Glu1184Ter nonsense NM_001365684.2:c.2676dup NP_001352613.2:p.Glu893Terfs frameshift nonsense NM_001409301.1:c.3549dup NP_001396230.1:p.Glu1184Terfs frameshift nonsense NM_001409302.1:c.3549dup NP_001396231.1:p.Glu1184Terfs frameshift nonsense NM_001409303.1:c.3549dup NP_001396232.1:p.Glu1184Terfs frameshift nonsense NM_001409304.1:c.3129dup NP_001396233.1:p.Glu1044Terfs frameshift nonsense NM_001409305.1:c.2796dup NP_001396234.1:p.Glu933Terfs frameshift nonsense NM_001409306.1:c.2676dup NP_001396235.1:p.Glu893Terfs frameshift nonsense NM_001409307.1:c.2676dup NP_001396236.1:p.Glu893Terfs frameshift nonsense NM_001409308.1:c.2676dup NP_001396237.1:p.Glu893Terfs frameshift nonsense NM_001409309.1:c.2676dup NP_001396238.1:p.Glu893Terfs frameshift nonsense NM_022455.4:c.3549dupT frameshift nonsense NM_172349.5:c.2676dup NP_758859.2:p.Glu893Terfs frameshift nonsense NC_000005.10:g.177211948dup NC_000005.9:g.176638949dup NG_009821.1:g.83870dup LRG_512:g.83870dup LRG_512t1:c.3549dup LRG_512p1:p.Glu1184Terfs - Protein change
- E1184*, E915*
- Other names
- -
- Canonical SPDI
- NC_000005.10:177211947:T:TT
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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
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| NSD1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1757 | 1874 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 1, 2024 | RCV000414581.18 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 14, 2022 | RCV003231380.9 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Feb 08, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Sotos syndrome 1
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000248323.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
|
|
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Pathogenic
(Jul 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Sotos syndrome
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002054927.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
|
|
|
Pathogenic
(Feb 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
None
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002097289.1
First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022 |
Comment:
The c.3549dup;p.(Glu1184*) is a null frameshift variant in the NSD1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant … (more)
The c.3549dup;p.(Glu1184*) is a null frameshift variant in the NSD1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 211726; PMID: 12464997; 15942875; 16247291; 22924495; 28475857) - PS4. This variant is not present in population databases (rs797045813, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
|
|
|
Pathogenic
(Sep 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
None
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001403951.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu1184*) in the NSD1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Glu1184*) in the NSD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NSD1 are known to be pathogenic (PMID: 12464997, 14571271, 15942875, 16247291). This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Sotos syndrome (PMID: 15942875, 22924495, 28475857). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 211726). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Apr 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000490674.4
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant … (more)
Nonsense variant predicted to result in nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30952489, 28475857, 12464997, 22924495, 34374989) (less)
|
|
|
Pathogenic
(May 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005050548.5
First in ClinVar: Jun 17, 2024 Last updated: Oct 20, 2024 |
Comment:
NSD1: PVS1, PS2, PM2, PS4:Moderate
Number of individuals with the variant: 1
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Glu1184*) in the NSD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NSD1 are known to be pathogenic (PMID: 12464997, 14571271, 15942875, 16247291). This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Sotos syndrome (PMID: 15942875, 22924495, 28475857). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 211726). For these reasons, this variant has been classified as Pathogenic.
Comment:
Nonsense variant predicted to result in nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30952489, 28475857, 12464997, 22924495, 34374989)
Comment:
NSD1: PVS1, PS2, PM2, PS4:Moderate
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. |
Comment:
The c.3549dup;p.(Glu1184*) is a null frameshift variant in the NSD1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 211726; PMID: 12464997; 15942875; 16247291; 22924495; 28475857) - PS4. This variant is not present in population databases (rs797045813, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Glu1184*) in the NSD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NSD1 are known to be pathogenic (PMID: 12464997, 14571271, 15942875, 16247291). This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Sotos syndrome (PMID: 15942875, 22924495, 28475857). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 211726). For these reasons, this variant has been classified as Pathogenic.
Comment:
Nonsense variant predicted to result in nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30952489, 28475857, 12464997, 22924495, 34374989)
Comment:
NSD1: PVS1, PS2, PM2, PS4:Moderate
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability. | Tatton-Brown K | American journal of human genetics | 2017 | PMID: 28475857 |
| Translation of a research-based genetic test on a rare syndrome into clinical service testing, with sotos syndrome as an example. | Pohjola P | Genetic testing and molecular biomarkers | 2012 | PMID: 22924495 |
| 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 |
| Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes. | Türkmen S | European journal of human genetics : EJHG | 2003 | PMID: 14571271 |
| 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 rs797045813 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.