ClinVar Genomic variation as it relates to human health
NM_030632.3(ASXL3):c.3106C>T (p.Arg1036Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_030632.3(ASXL3):c.3106C>T (p.Arg1036Ter)
Variation ID: 429913 Accession: VCV000429913.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 18q12.1 18: 33742954 (GRCh38) [ NCBI UCSC ] 18: 31322918 (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 Jul 2, 2017 Feb 14, 2024 Aug 19, 2022 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_030632.3:c.3106C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_085135.1:p.Arg1036Ter nonsense NC_000018.10:g.33742954C>T NC_000018.9:g.31322918C>T NG_055244.1:g.169378C>T - Protein change
- R1036*
- Other names
- -
- Canonical SPDI
- NC_000018.10:33742953:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- protein truncation Variation Ontology [VariO:0015]
-
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.
-
-
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. |
|||
ASXL3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
675 | 716 |
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 19, 2022 | RCV000493532.13 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
May 26, 2021 | RCV000509007.10 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Sep 29, 2017)
|
criteria provided, single submitter
Method: research
|
Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute for Genomic Medicine, Nationwide Children's Hospital
Study: Rare Disease Genomics
Accession: SCV000605939.1 First in ClinVar: Oct 04, 2017 Last updated: Oct 04, 2017 |
Comment:
The p.R1036X variant is predicted to cause loss of function as it introduces a stop codon at amino acid 1036, truncating the protein to 46% … (more)
The p.R1036X variant is predicted to cause loss of function as it introduces a stop codon at amino acid 1036, truncating the protein to 46% of its wild-type length. It is not observed in 122,882 individuals of various ancestries in the gnomAD database, indicating it is not a common benign variant in those populations. It has been previously reported as a likely pathogenic variant, though the patient phenotype was not provided. We interpret p.R1036X as a pathogenic variant. (less)
Age: 10-19 years
Sex: female
Ethnicity/Population group: Caucasian
Geographic origin: United States
Method: Reads were aligned to the GRCh37 reference sequence and variants were called using GATK best practices. The variant was manually reviewed in IGV and its de novo status was confirmed by Sanger sequencing.
|
|
Pathogenic
(Nov 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV000890008.1
First in ClinVar: Oct 04, 2017 Last updated: Oct 04, 2017 |
|
|
Pathogenic
(Jul 10, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome
Affected status: yes
Allele origin:
de novo
|
Genetics Laboratory - UDIAT Centre Diagnòstic, Hospital Universitari Parc Tauli
Accession: SCV000930702.1
First in ClinVar: Aug 18, 2019 Last updated: Aug 18, 2019 |
Clinical Features:
Angelman-like syndrome (present) , dental anomalies (present)
|
|
Likely pathogenic
(Jun 17, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449863.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Jan 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV001451596.1
First in ClinVar: Dec 26, 2020 Last updated: Dec 26, 2020 |
Comment:
The ASXL3 c.3106C>T (p.Arg1036Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. This variant has been … (more)
The ASXL3 c.3106C>T (p.Arg1036Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. This variant has been previously reported in four individuals with Bainbridge-Ropers syndrome, including a sibling pair (Kuechler et al. 2017; Koboldt et al. 2018; Myers et al. 2018). In two cases, the p.Arg1036Ter variant is described as occurring de novo (Kuechler et al. 2017; Myers et al. 2018) and, in the family with two affected children, recurrence was attributed to presumed germline mosaicism as both parents were unaffected and did not carry the variant (Koboldt et al. 2018). The p.Arg1036Ter variant is not found in the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Based on the predicted truncating nature of the variant, its rarity, and identification in a de novo state, the p.Arg1036Ter variant is classified as pathogenic for Bainbridge-Ropers syndrome. (less)
|
|
Pathogenic
(May 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome
Affected status: yes
Allele origin:
de novo
|
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University
Accession: SCV001622409.1
First in ClinVar: May 23, 2021 Last updated: May 23, 2021 |
Clinical Features:
Global developmental delay (present) , Intellectual disability (present) , Delayed speech and language development (present) , Cognitive impairment (present) , Severe muscular hypotonia (present) , … (more)
Global developmental delay (present) , Intellectual disability (present) , Delayed speech and language development (present) , Cognitive impairment (present) , Severe muscular hypotonia (present) , Inability to walk (present) (less)
|
|
Pathogenic
(May 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512658.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PVS1 strong, PS4 moderate, PM2 moderate, PM6 moderate
Geographic origin: Brazil
|
|
Pathogenic
(Aug 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000582599.5
First in ClinVar: Jul 02, 2017 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 1213 amino acids are lost, and other loss-of-function variants have been … (more)
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 1213 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31332282, 34653234, 34436830, 29367179, 27901041, 29305346, 27824329, 25363760, 28191890, 28714951, 31981491, 33751541, 32565546, 28191889, 33004838, 34015165) (less)
|
|
Pathogenic
(Apr 26, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001198399.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with clinical features of Bainbridge-Ropers syndrome (PMID: 27901041, … (more)
For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with clinical features of Bainbridge-Ropers syndrome (PMID: 27901041, 29305346, 29367179, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 429913). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the ASXL3 gene (p.Arg1036*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1213 amino acids of the ASXL3 protein. (less)
|
|
Pathogenic
(Aug 06, 2018)
|
no assertion criteria provided
Method: provider interpretation
|
Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome
Affected status: yes
Allele origin:
de novo
|
GenomeConnect - Simons Searchlight
Accession: SCV001443578.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-08-06 and interpreted as Pathogenic. The reporting laboratory … (more)
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-08-06 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. (less)
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Caesarian section (present) , Neonatal respiratory distress (present) , Strabismus (present) , Generalized hypotonia (present) , Gastroesophageal reflux (present) , Abnormal heart morphology (present) , … (more)
Caesarian section (present) , Neonatal respiratory distress (present) , Strabismus (present) , Generalized hypotonia (present) , Gastroesophageal reflux (present) , Abnormal heart morphology (present) , Patent ductus arteriosus (present) , Abnormality of the cardiovascular system (present) (less)
Age: 0-9 years
Sex: female
Testing laboratory: Not Provided
Date variant was reported to submitter: 2018-03-24
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Autistic behavior (present) , Caesarian section (present) , Poor suck (present) , Feeding difficulties in infancy (present) , Generalized hypotonia (present) , Microcephaly (present) , … (more)
Autistic behavior (present) , Caesarian section (present) , Poor suck (present) , Feeding difficulties in infancy (present) , Generalized hypotonia (present) , Microcephaly (present) , Gastroesophageal reflux (present) , Pneumonia (present) , Failure to thrive (present) , Short stature (present) , Abnormality of the skeletal system (present) , Scoliosis (present) , Osteoporosis (present) (less)
Age: 10-19 years
Sex: male
Testing laboratory: Molecular Diagnostics Laboratory,Hospital Sainte-Justine
Date variant was reported to submitter: 2016-08-17
Testing laboratory interpretation: Pathogenic
|
Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
---|---|---|---|---|
protein truncation
|
|
|
Institute for Genomic Medicine, Nationwide Children's Hospital
Study: Rare Disease Genomics Accession: SCV000605939.1
|
|
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Childhood-onset generalized epilepsy in Bainbridge-Ropers syndrome. | Myers KA | Epilepsy research | 2018 | PMID: 29367179 |
A de novo nonsense mutation in ASXL3 shared by siblings with Bainbridge-Ropers syndrome. | Koboldt DC | Cold Spring Harbor molecular case studies | 2018 | PMID: 29305346 |
Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition. | Kuechler A | European journal of human genetics : EJHG | 2017 | PMID: 27901041 |
Text-mined citations for this variant ...
HelpRecord last updated Feb 14, 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.