VCV000521454.40 - ClinVar

NM_003011.4(SET):c.130_133del (p.Arg44fs)

Germline

Classification

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.

(10)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003011.4(SET):c.130_133del (p.Arg44fs)

Variation ID: 521454 Accession: VCV000521454.40

Type and length

Deletion, 4 bp

Location

Cytogenetic: 9q34.11 9: 128691222-128691225 (GRCh38) [ NCBI UCSC ] 9: 131453501-131453504 (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	Apr 15, 2018	Oct 20, 2024	Jan 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_003011.4:c.128_131del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_003011.4:c.130_133del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003002.2:p.Arg44fs	frameshift
NM_001122821.1:c.165_168delAGAC
NM_001122821.1:c.167_170delACAG
NM_001122821.2:c.169_172del	NP_001116293.1:p.Arg57fs	frameshift
NM_001248000.2:c.103_106del	NP_001234929.1:p.Arg35fs	frameshift
NM_001248000.2:c.99_102delAGAC
NM_001248001.2:c.97_100del	NP_001234930.1:p.Arg33fs	frameshift
NM_001374326.1:c.169_172del	NP_001361255.1:p.Arg57fs	frameshift
NC_000009.12:g.128691224_128691227del
NC_000009.11:g.131453503_131453506del
NG_030356.1:g.12570_12573del

... more HGVS ... less HGVS

Protein change

R44fs, R35fs, R33fs, R57fs

Other names

Canonical SPDI

NC_000009.12:128691221:AGACAG:AG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA658773419 OMIM: 600960.0001 dbSNP: rs1554776342 VarSome

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
Gene	OMIM	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.
SET		-	-	GRCh38 GRCh37	77	126

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.
Intellectual disability, autosomal dominant 58	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Apr 18, 2022	RCV000678248.12
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Dec 29, 2016	RCV000622364.4
Global developmental delay	Pathogenic (1)	criteria provided, single submitter	-	RCV001526660.4
Intellectual disability	Pathogenic (1)	criteria provided, single submitter	Jan 13, 2023	RCV003106006.6
SET-related disorder	not provided (1)	no classification provided	-	RCV003325969.4
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 10, 2022	RCV001008142.23

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 (Oct 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 58 Affected status: yes Allele origin: unknown	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV001976659.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021	Publications: PubMed (1) PubMed: 34008892 Comment: PVS1, PM2, PP3
Pathogenic (Jun 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 58 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002020074.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Likely pathogenic (Nov 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002063262.20 First in ClinVar: Jan 22, 2022 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Apr 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 58 Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002568279.1 First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022	Comment: PVS1, PS4_Moderate, PM2, PM6
Pathogenic (Jan 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability Affected status: yes Allele origin: de novo	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV003761537.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023
Pathogenic (Dec 29, 2016)	criteria provided, single submitter (ambry_reporting_categories_2017) Method: clinical testing	Hereditary disease Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000742048.2 First in ClinVar: Apr 15, 2018 Last updated: Dec 11, 2022	Publications: PubMed (3) PubMed: 25356899‚ 11231286‚ 27775603 Comment: Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected Clinical Features: MR/ID/DD (present) , Brain MRI positive (present) , Hypotonia (present) , Neurologic (child onset) (present) Family history: yes Sex: male Ethnicity/Population group: European-origin,Asian-origin Segregation observed: yes
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Global developmental delay Affected status: yes Allele origin: de novo	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV001737092.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021
Pathogenic (Jan 10, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001167902.3 First in ClinVar: Mar 16, 2020 Last updated: Mar 04, 2023	Comment: Frameshift 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 … (more) Frameshift 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29907757, 28135719, 28191890, 29688601, 31785789) (less)
Pathogenic (Apr 29, 2022)	no assertion criteria provided Method: literature only	INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 58 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000804271.2 First in ClinVar: Sep 03, 2018 Last updated: Jun 09, 2024	Publications: PubMed (2) PubMed: 29688601‚ 28135719 Comment on evidence: In a 16-year-old boy and his 49-year-old mother (patients 1a and 1b) with autosomal dominant intellectual developmental disorder-58 (MRD58; 618106), Stevens et al. (2018) identified … (more) In a 16-year-old boy and his 49-year-old mother (patients 1a and 1b) with autosomal dominant intellectual developmental disorder-58 (MRD58; 618106), Stevens et al. (2018) identified a heterozygous 4-bp deletion (c.167_170del, NM_001122821.1) in exon 2 of the SET gene, predicted to result in a frameshift and premature termination (Arg57LeufsTer10). The mutation, which was found by whole-exome sequencing, occurred de novo in the mother. Stevens et al. (2018) noted that the same de novo heterozygous 4-bp deletion in the SET gene had previously been found in 2 unrelated patients with intellectual disability in the Deciphering Developmental Disorders Study (2017). Functional studies of the variant and studies of patient cells were not performed; however, the variant was predicted to result in a loss of function and haploinsufficiency. (less)
not provided (-)	no classification provided Method: phenotyping only	SET-Related Disorder Affected status: yes Allele origin: de novo	GenomeConnect - Brain Gene Registry Accession: SCV004032155.1 First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023	Comment: Variant interpreted as Pathogenic and reported on 02-13-2020 by Lab GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect … (more) Variant interpreted as Pathogenic and reported on 02-13-2020 by Lab GeneDx. 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) Clinical Features: Obesity (present) , Short stature (present) , Decreased response to growth hormone stimulation test (present) , Myopia (present) , Abnormal optic nerve morphology (present) , … (more) Obesity (present) , Short stature (present) , Decreased response to growth hormone stimulation test (present) , Myopia (present) , Abnormal optic nerve morphology (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Autistic behavior (present) , Motor stereotypies (present) , Anxiety (present) , Short attention span (present) , Abnormality of facial musculature (present) , Abnormal muscle physiology (present) , Feeding difficulties (present) , Abnormal esophagus morphology (present) , Abnormality of the bladder (present) (less) Indication for testing: Diagnostic Age: 10-19 years Sex: female Method: Gene Panel Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2020-02-13 Testing laboratory interpretation: Pathogenic

Comment:

Frameshift 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29907757, 28135719, 28191890, 29688601, 31785789)

Comment:

Variant interpreted as Pathogenic and reported on 02-13-2020 by Lab GeneDx. 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders.	Marinakis NM	American journal of medical genetics. Part A	2021	PMID: 34008892
De novo mutations in the SET nuclear proto-oncogene, encoding a component of the inhibitor of histone acetyltransferases (INHAT) complex in patients with nonsyndromic intellectual disability.	Stevens SJC	Human mutation	2018	PMID: 29688601
Prevalence and architecture of de novo mutations in developmental disorders.	Deciphering Developmental Disorders Study	Nature	2017	PMID: 28135719
Zinc Finger and X-Linked Factor (ZFX) Binds to Human SET Transcript 2 Promoter and Transactivates SET Expression.	Xu S	International journal of molecular sciences	2016	PMID: 27775603
De novo mutations in moderate or severe intellectual disability.	Hamdan FF	PLoS genetics	2014	PMID: 25356899
Identification and characterization of SEB, a novel protein that binds to the acute undifferentiated leukemia-associated protein SET.	Minakuchi M	European journal of biochemistry	2001	PMID: 11231286

Text-mined citations for rs1554776342 ...

These 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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_003011.4(SET):c.130_133del (p.Arg44fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1554776342 ...