Frameshift variant predicted to result in protein truncation, as the last 600 amino acids are replaced with 51 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17565729, 15942875)
ClinVar Genomic variation as it relates to human health
NM_022455.5(NSD1):c.6291_6294del (p.Lys2097fs)
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.
(3)
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/Likely pathogenic
3
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.6291_6294del (p.Lys2097fs)
Variation ID: 1215538 Accession: VCV001215538.9
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 5q35.3 5: 177291983-177291986 (GRCh38) [ NCBI UCSC ] 5: 176718984-176718987 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Sep 8, 2021 Dec 24, 2023 Sep 15, 2021 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_022455.5:c.6291_6294del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_071900.2:p.Lys2097fs frameshift NM_001365684.2:c.5418_5421delGAAA NP_001352613.2:p.Lys1806Asnfs frameshift NM_001409301.1:c.6291_6294delGAAA NP_001396230.1:p.Lys2097Asnfs frameshift NM_001409302.1:c.6291_6294delGAAA NP_001396231.1:p.Lys2097Asnfs frameshift NM_001409303.1:c.6291_6294delGAAA NP_001396232.1:p.Lys2097Asnfs frameshift NM_001409304.1:c.5871_5874delGAAA NP_001396233.1:p.Lys1957Asnfs frameshift NM_001409305.1:c.5538_5541delGAAA NP_001396234.1:p.Lys1846Asnfs frameshift NM_001409306.1:c.5529_5532delGAAA NP_001396235.1:p.Lys1843Asnfs frameshift NM_001409307.1:c.5529_5532delGAAA NP_001396236.1:p.Lys1843Asnfs frameshift NM_001409308.1:c.5418_5421delGAAA NP_001396237.1:p.Lys1806Asnfs frameshift NM_001409309.1:c.5169_5172delGAAA NP_001396238.1:p.Lys1723Asnfs frameshift NM_022455.4:c.6291_6294del NM_022455.4:c.6291_6294delGAAA NP_071900.2:p.Lys2097Asnfs frameshift NM_172349.5:c.5418_5421delGAAA NP_758859.2:p.Lys1806Asnfs frameshift NC_000005.10:g.177291986_177291989del NC_000005.9:g.176718987_176718990del NG_009821.1:g.163908_163911del LRG_512:g.163908_163911del LRG_512t1:c.6291_6294del LRG_512p1:p.Lys2097Asnfs - Protein change
- K1828fs, K2097fs
- Other names
- -
- Canonical SPDI
- NC_000005.10:177291982:AAAGAAA:AAA
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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 |
1737 | 1852 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
criteria provided, single submitter
|
May 3, 2021 | RCV001585420.10 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Sep 15, 2021 | RCV003232389.11 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(May 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001819327.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Frameshift variant predicted to result in protein truncation, as the last 600 amino acids are replaced with 51 different amino acids, and other loss-of-function variants … (more)
Frameshift variant predicted to result in protein truncation, as the last 600 amino acids are replaced with 51 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17565729, 15942875) (less)
|
|
|
Pathogenic
(Sep 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
None
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002107886.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change creates a premature translational stop signal (p.Lys2097Asnfs*52) in the NSD1 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Lys2097Asnfs*52) in the NSD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 600 amino acid(s) of the NSD1 protein. 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, 17565729). In at least one individual the variant was observed to be de novo. This variant is also known as 6291-4delGAAA. This variant disrupts a region of the NSD1 protein in which other variant(s) (p.Cys2202Tyr) have been determined to be pathogenic (PMID: 16222665, 25533962, 29276005; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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not provided
(-)
|
no classification provided
Method: phenotyping only
|
Sotos syndrome
Affected status: unknown
Allele origin:
paternal
|
GenomeConnect - Brain Gene Registry
Accession: SCV004032183.2
First in ClinVar: Sep 09, 2023 Last updated: Dec 24, 2023 |
Comment:
Variant classified as Pathogenic and reported on 12-15-2022 by Invitae. This variant was identified in multiple related participants enrolled in GenomeConnect. Phenotypic data from the … (more)
Variant classified as Pathogenic and reported on 12-15-2022 by Invitae. This variant was identified in multiple related participants enrolled in GenomeConnect. Phenotypic data from the proband has been submitted with this variant. Additional phenotypic information for family members might be available from GenomeConnect. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less)
Observation 1:
Clinical Features:
Overgrowth (present) , Tall stature (present) , Abnormality of eye movement (present) , Hypermetropia (present) , Feeding difficulties (present) , Abnormal esophagus morphology (present) , … (more)
Overgrowth (present) , Tall stature (present) , Abnormality of eye movement (present) , Hypermetropia (present) , Feeding difficulties (present) , Abnormal esophagus morphology (present) , Abnormal large intestine morphology (present) , Abnormality of the bladder (present) , Abnormal number of teeth (present) , Tooth malposition (present) (less)
Indication for testing: Family Testing
Age: 10-19 years
Sex: female
Method: Single Gene Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2023-04-14
Testing laboratory interpretation: Pathogenic
Observation 2:
Clinical Features:
Abnormality of the amniotic fluid (present) , Decreased fetal movement (present) , Overgrowth (present) , Obesity (present) , Tall stature (present) , Hearing impairment (present) … (more)
Abnormality of the amniotic fluid (present) , Decreased fetal movement (present) , Overgrowth (present) , Obesity (present) , Tall stature (present) , Hearing impairment (present) , Tinnitus (present) , Hyperacusis (present) , Hyperhidrosis (present) , Abnormal pattern of respiration (present) , Tooth malposition (present) (less)
Indication for testing: Diagnostic
Age: 10-19 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2022-12-15
Testing laboratory interpretation: Pathogenic
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Lys2097Asnfs*52) in the NSD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 600 amino acid(s) of the NSD1 protein. 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, 17565729). In at least one individual the variant was observed to be de novo. This variant is also known as 6291-4delGAAA. This variant disrupts a region of the NSD1 protein in which other variant(s) (p.Cys2202Tyr) have been determined to be pathogenic (PMID: 16222665, 25533962, 29276005; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant classified as Pathogenic and reported on 12-15-2022 by Invitae. This variant was identified in multiple related participants enrolled in GenomeConnect. Phenotypic data from the proband has been submitted with this variant. Additional phenotypic information for family members might be available from GenomeConnect. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
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:
Frameshift variant predicted to result in protein truncation, as the last 600 amino acids are replaced with 51 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17565729, 15942875)
Comment:
This sequence change creates a premature translational stop signal (p.Lys2097Asnfs*52) in the NSD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 600 amino acid(s) of the NSD1 protein. 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, 17565729). In at least one individual the variant was observed to be de novo. This variant is also known as 6291-4delGAAA. This variant disrupts a region of the NSD1 protein in which other variant(s) (p.Cys2202Tyr) have been determined to be pathogenic (PMID: 16222665, 25533962, 29276005; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant classified as Pathogenic and reported on 12-15-2022 by Invitae. This variant was identified in multiple related participants enrolled in GenomeConnect. Phenotypic data from the proband has been submitted with this variant. Additional phenotypic information for family members might be available from GenomeConnect. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
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 |
| Large-scale discovery of novel genetic causes of developmental disorders. | Deciphering Developmental Disorders Study | Nature | 2015 | PMID: 25533962 |
| Heterogeneity of NSD1 alterations in 116 patients with Sotos syndrome. | Saugier-Veber P | Human mutation | 2007 | PMID: 17565729 |
| Familial gigantism caused by an NSD1 mutation. | van Haelst MM | American journal of medical genetics. Part A | 2005 | PMID: 16222665 |
| 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 |
Text-mined citations for rs2127276046 ...
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 Oct 27, 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.