Nonsense variant predicted to result in protein truncation or 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: 25525159, 31785789, 29276005, 28475857, 15942875)
ClinVar Genomic variation as it relates to human health
NM_022455.5(NSD1):c.1831C>T (p.Arg611Ter)
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.
(7)
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
7
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.1831C>T (p.Arg611Ter)
Variation ID: 159273 Accession: VCV000159273.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q35.3 5: 177210230 (GRCh38) [ NCBI UCSC ] 5: 176637231 (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 Apr 9, 2023 Mar 30, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_022455.5:c.1831C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_071900.2:p.Arg611Ter nonsense NM_001365684.2:c.958C>T NP_001352613.2:p.Arg320Ter nonsense NM_001409301.1:c.1831C>T NP_001396230.1:p.Arg611Ter nonsense NM_001409302.1:c.1831C>T NP_001396231.1:p.Arg611Ter nonsense NM_001409303.1:c.1831C>T NP_001396232.1:p.Arg611Ter nonsense NM_001409304.1:c.1411C>T NP_001396233.1:p.Arg471Ter nonsense NM_001409305.1:c.1078C>T NP_001396234.1:p.Arg360Ter nonsense NM_001409306.1:c.958C>T NP_001396235.1:p.Arg320Ter nonsense NM_001409307.1:c.958C>T NP_001396236.1:p.Arg320Ter nonsense NM_001409308.1:c.958C>T NP_001396237.1:p.Arg320Ter nonsense NM_001409309.1:c.958C>T NP_001396238.1:p.Arg320Ter nonsense NM_172349.5:c.958C>T NP_758859.2:p.Arg320Ter nonsense NC_000005.10:g.177210230C>T NC_000005.9:g.176637231C>T NG_009821.1:g.82152C>T LRG_512:g.82152C>T LRG_512t1:c.1831C>T LRG_512p1:p.Arg611Ter - Protein change
- R611*, R342*, R320*, R471*, R360*
- Other names
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- Canonical SPDI
- NC_000005.10:177210229:C:T
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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.
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- 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 (1) |
criteria provided, single submitter
|
Mar 30, 2023 | RCV000294223.10 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2021 | RCV003231177.10 |
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
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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|---|---|---|---|---|---|
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Pathogenic
(Mar 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329435.6
First in ClinVar: Dec 06, 2016 Last updated: Apr 09, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or 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: 25525159, 31785789, 29276005, 28475857, 15942875) (less)
|
|
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Pathogenic
(Feb 08, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Sotos syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000194096.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
|
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Pathogenic
(Jan 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
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Sotos syndrome
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV000886722.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
Comment:
This NSD1 variant has been previous been reported in individuals with a clinical presentation consistent with Sotos syndrome. Two submitters in ClinVar classify this variant … (more)
This NSD1 variant has been previous been reported in individuals with a clinical presentation consistent with Sotos syndrome. Two submitters in ClinVar classify this variant as pathogenic. Additionally this variant is absent from large population datasets. This nonsense variant in exon 5 of 23 likely results in nonsense-mediated decay and lack of protein production. This variant is considered pathogenic. (less)
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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
|
Genome-Nilou Lab
Accession: SCV002054914.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
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Pathogenic
(Sep 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
None
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002247256.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg611*) 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.Arg611*) 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: 28475857, 29276005). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 159273). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Sotos syndrome
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512628.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate, PM6 strong
Geographic origin: Brazil
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Pathogenic
(Jan 01, 2019)
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no assertion criteria provided
Method: clinical testing
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Sotos syndrome 1
Affected status: yes
Allele origin:
de novo
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Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV001427830.1
First in ClinVar: Aug 13, 2020 Last updated: Aug 13, 2020 |
|
Comment:
Comment:
This NSD1 variant has been previous been reported in individuals with a clinical presentation consistent with Sotos syndrome. Two submitters in ClinVar classify this variant as pathogenic. Additionally this variant is absent from large population datasets. This nonsense variant in exon 5 of 23 likely results in nonsense-mediated decay and lack of protein production. This variant is considered pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg611*) 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: 28475857, 29276005). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 159273). For these reasons, this variant has been classified as Pathogenic.
Comment:
ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate, PM6 strong
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:
Nonsense variant predicted to result in protein truncation or 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: 25525159, 31785789, 29276005, 28475857, 15942875)
Comment:
This NSD1 variant has been previous been reported in individuals with a clinical presentation consistent with Sotos syndrome. Two submitters in ClinVar classify this variant as pathogenic. Additionally this variant is absent from large population datasets. This nonsense variant in exon 5 of 23 likely results in nonsense-mediated decay and lack of protein production. This variant is considered pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg611*) 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: 28475857, 29276005). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 159273). For these reasons, this variant has been classified as Pathogenic.
Comment:
ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate, PM6 strong
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders. | Faundes V | American journal of human genetics | 2018 | PMID: 29276005 |
| 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 |
| 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 | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
| 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 rs587784077 ...
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.