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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24859339, 25138099, 28263952, 28990276, 28191890, 23020937, 31785789, 32299058)
ClinVar Genomic variation as it relates to human health
NM_001080517.3(SETD5):c.2302C>T (p.Arg768Ter)
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.
(8)
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001080517.3(SETD5):c.2302C>T (p.Arg768Ter)
Variation ID: 219198 Accession: VCV000219198.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.3 3: 9448586 (GRCh38) [ NCBI UCSC ] 3: 9490270 (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 Jan 18, 2016 Nov 30, 2024 Oct 11, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001080517.3:c.2302C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001073986.1:p.Arg768Ter nonsense NM_001292043.2:c.2008C>T NP_001278972.1:p.Arg670Ter nonsense NM_001349451.2:c.2008C>T NP_001336380.1:p.Arg670Ter nonsense NC_000003.12:g.9448586C>T NC_000003.11:g.9490270C>T NG_034132.1:g.55887C>T - Protein change
- R768*, R670*
- Other names
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- Canonical SPDI
- NC_000003.12:9448585: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. |
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| SETD5 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1074 | 1142 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
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Oct 11, 2024 | RCV000203577.12 | |
| Pathogenic (1) |
criteria provided, single submitter
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Apr 2, 2020 | RCV001374941.1 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 29, 2023 | RCV001562177.7 |
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
(Feb 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
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Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001430123.1
First in ClinVar: Aug 21, 2020 Last updated: Aug 21, 2020 |
Clinical Features:
Global developmental delay (present) , Hypotonia (present) , Mild short stature (present)
Sex: female
Tissue: blood
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Pathogenic
(Apr 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental disorder
Affected status: yes
Allele origin:
germline
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Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV001572229.1
First in ClinVar: Apr 28, 2021 Last updated: Apr 28, 2021 |
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Pathogenic
(Jan 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency
Affected status: yes
Allele origin:
unknown
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Daryl Scott Lab, Baylor College of Medicine
Accession: SCV002072587.1
First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022 |
Number of individuals with the variant: 1
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Pathogenic
(Feb 15, 2022)
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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: SCV001784904.3
First in ClinVar: Aug 14, 2021 Last updated: Mar 04, 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 disease; Not … (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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24859339, 25138099, 28263952, 28990276, 28191890, 23020937, 31785789, 32299058) (less)
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Pathogenic
(Oct 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003525088.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg768*) in the SETD5 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg768*) in the SETD5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SETD5 are known to be pathogenic (PMID: 24680889). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of SETD5-related neurodevelopmental disorder (PMID: 25138099, 28990276). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 219198). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency
(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: SCV005399718.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.5, 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_v1.3.5, 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 intellectual developmental disorder, autosomal dominant 23 (MIM#615761). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants have been reported as pathogenic and likely-pathogenic (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic or likely pathogenic in multiple individuals, including five individuals in whom the variant was de novo (PMIDs: 25138099, 23020937, 28990276, ClinVar, DECIPHER). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency
Affected status: yes
Allele origin:
germline
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Juno Genomics, Hangzhou Juno Genomics, Inc
Accession: SCV005417891.1
First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024 |
Comment:
PM2_Supporting+PS2_Supporting+PVS1+PS4_Supporting
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Pathogenic
(Nov 10, 2012)
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no assertion criteria provided
Method: literature only
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INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 23
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000258924.3
First in ClinVar: Jan 18, 2016 Last updated: Mar 12, 2022 |
Comment on evidence:
In a patient with autosomal dominant intellectual developmental disorder-23 (MRD23; 615761), Rauch et al. (2012) identified a de novo heterozygous c.2302C-T transition (c.2302C-T, NM_001080517.1) in … (more)
In a patient with autosomal dominant intellectual developmental disorder-23 (MRD23; 615761), Rauch et al. (2012) identified a de novo heterozygous c.2302C-T transition (c.2302C-T, NM_001080517.1) in the SETD5 gene, resulting in an arg768-to-ter (R768X) substitution. The mutation was predicted to cause nonsense-mediated mRNA decay. The patient was ascertained from a cohort of 51 patients with intellectual disability who underwent exome sequencing. Rauch et al. (2012) postulated haploinsufficiency as the disease mechanism. (less)
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Arg768*) in the SETD5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SETD5 are known to be pathogenic (PMID: 24680889). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of SETD5-related neurodevelopmental disorder (PMID: 25138099, 28990276). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 219198). For these reasons, this variant has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.5, 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 intellectual developmental disorder, autosomal dominant 23 (MIM#615761). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants have been reported as pathogenic and likely-pathogenic (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic or likely pathogenic in multiple individuals, including five individuals in whom the variant was de novo (PMIDs: 25138099, 23020937, 28990276, ClinVar, DECIPHER). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
PM2_Supporting+PS2_Supporting+PVS1+PS4_Supporting
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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24859339, 25138099, 28263952, 28990276, 28191890, 23020937, 31785789, 32299058)
Comment:
This sequence change creates a premature translational stop signal (p.Arg768*) in the SETD5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SETD5 are known to be pathogenic (PMID: 24680889). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of SETD5-related neurodevelopmental disorder (PMID: 25138099, 28990276). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 219198). For these reasons, this variant has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.5, 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 intellectual developmental disorder, autosomal dominant 23 (MIM#615761). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants have been reported as pathogenic and likely-pathogenic (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic or likely pathogenic in multiple individuals, including five individuals in whom the variant was de novo (PMIDs: 25138099, 23020937, 28990276, ClinVar, DECIPHER). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
PM2_Supporting+PS2_Supporting+PVS1+PS4_Supporting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Identifying phenotypic expansions for congenital diaphragmatic hernia plus (CDH+) using DECIPHER data. | Hardcastle A | American journal of medical genetics. Part A | 2022 | PMID: 35904974 |
| Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability. | Zhao JJ | American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics | 2018 | PMID: 28990276 |
| Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome. | Kuechler A | European journal of human genetics : EJHG | 2015 | PMID: 25138099 |
| De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability. | Grozeva D | American journal of human genetics | 2014 | PMID: 24680889 |
| Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. | Rauch A | Lancet (London, England) | 2012 | PMID: 23020937 |
Text-mined citations for rs864321657 ...
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 30, 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.