VCV000279694.12 - ClinVar

NM_030632.3(ASXL3):c.3349C>T (p.Arg1117Ter)

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.

(8)

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_030632.3(ASXL3):c.3349C>T (p.Arg1117Ter)

Variation ID: 279694 Accession: VCV000279694.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q12.1 18: 33743197 (GRCh38) [ NCBI UCSC ] 18: 31323161 (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	Dec 6, 2016	Mar 23, 2024	Mar 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_030632.3:c.3349C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_085135.1:p.Arg1117Ter	nonsense
NC_000018.10:g.33743197C>T
NC_000018.9:g.31323161C>T
NG_055244.1:g.169621C>T

Protein change

R1117*

Other names

Canonical SPDI

NC_000018.10:33743196:C:T

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: CA10603417 dbSNP: rs868044680 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.
ASXL3		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	770	811

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.
Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Mar 11, 2024	RCV000263069.8
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 19, 2019	RCV000271358.7

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.
Likely pathogenic (Nov 05, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000336692.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ASXL3 Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Sep 19, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329090.5 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Comment: Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 1132 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 1132 amino acids are lost, 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: 28362156, 26633542, 29429203, 33258288) (less)
Pathogenic (Nov 25, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV003806916.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 moderated Number of individuals with the variant: 1 Clinical Features: Thin upper lip vermilion (present) , Diastasis recti (present) , Microcephaly (present) , Strabismus (present) , Anxiety (present) , Long eyelashes (present) , Decreased body … (more) Thin upper lip vermilion (present) , Diastasis recti (present) , Microcephaly (present) , Strabismus (present) , Anxiety (present) , Long eyelashes (present) , Decreased body weight (present) , Narrow forehead (present) , Short stature (present) , Global developmental delay (present) , Hypertelorism (present) , Highly arched eyebrow (present) , Bulbous nose (present) , Smooth philtrum (present) , Synophrys (present) , Clinodactyly of the 5th finger (present) , Short philtrum (present) , Generalized hypertrichosis (present) , Prolonged neonatal jaundice (present) , Gestational diabetes (present) , Renal cyst (present) (less) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV000807288.3 First in ClinVar: Dec 06, 2016 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 25326635
Pathogenic (Mar 11, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) 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	Centre for Inherited Metabolic Diseases, Karolinska University Hospital Accession: SCV004708219.1 First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024
Likely pathogenic (Dec 01, 2021)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) 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: SCV004801622.1 First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024	Comment: The ASXL3 c.3349C>T p.(Arg1117Ter) nonsense variant occurs in the last exon of the gene and the resulting transcript may escape nonsense-mediated mRNA decay. This variant … (more) The ASXL3 c.3349C>T p.(Arg1117Ter) nonsense variant occurs in the last exon of the gene and the resulting transcript may escape nonsense-mediated mRNA decay. This variant has been identified in individuals with a phenotype consistent with Bainbridge-Ropers syndrome, including in a de novo state in at least one individual (Hedge et al. 2017; Zhang et al. 2018). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. Based on the available evidence, the c.3349C>T p.(Arg1117Ter) variant is classified as likely pathogenic for Bainbridge-Ropers syndrome. (less)
Pathogenic (Nov 30, 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, unknown	GenomeConnect - Simons Searchlight Accession: SCV001443485.1 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 2018-11-30 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 2018-11-30 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. (less) Observation 1: Number of individuals with the variant: 1 Sex: male Testing laboratory: GeneDx Date variant was reported to submitter: 2013-12-23 Testing laboratory interpretation: other Observation 2: Number of individuals with the variant: 1 Sex: female Testing laboratory: Azienda Ospedaliero Universitaria Date variant was reported to submitter: 2018-06-08 Testing laboratory interpretation: Pathogenic
Pathogenic (-)	no assertion criteria provided (ACMG Guidelines, 2015) Method: research	Bainbridge-Ropers syndrome Affected status: yes Allele origin: de novo	Pediatric Department, Xiangya Hospital, Central South University Accession: SCV004032217.1 First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023

Comment:

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 1132 amino acids are lost, 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: 28362156, 26633542, 29429203, 33258288)

Comment:

The ASXL3 c.3349C>T p.(Arg1117Ter) nonsense variant occurs in the last exon of the gene and the resulting transcript may escape nonsense-mediated mRNA decay. This variant has been identified in individuals with a phenotype consistent with Bainbridge-Ropers syndrome, including in a de novo state in at least one individual (Hedge et al. 2017; Zhang et al. 2018). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. Based on the available evidence, the c.3349C>T p.(Arg1117Ter) variant is classified as likely pathogenic for Bainbridge-Ropers syndrome.

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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ASXL3	-	-	-	-

Text-mined citations for rs868044680 ...

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 Mar 23, 2024

ClinVar Genomic variation as it relates to human health

NM_030632.3(ASXL3):c.3349C>T (p.Arg1117Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs868044680 ...