VCV000426927.17 - ClinVar

NM_015338.6(ASXL1):c.1934dup (p.Gly646fs)

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.

(12)

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_015338.6(ASXL1):c.1934dup (p.Gly646fs)

Variation ID: 426927 Accession: VCV000426927.17

Type and length

Duplication, 1 bp

Location

Cytogenetic: 20q11.21 20: 32434638-32434639 (GRCh38) [ NCBI UCSC ] 20: 31022441-31022442 (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	May 22, 2017	Oct 8, 2024	Mar 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_015338.6:c.1934dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_056153.2:p.Gly646fs	frameshift
NM_015338.6:c.1934dupG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001363734.1:c.1751dup	NP_001350663.1:p.Gly585fs	frameshift
NM_015338.5:c.1934dupG
NC_000020.11:g.32434646dup
NC_000020.10:g.31022449dup
NG_027868.1:g.81303dup
LRG_630:g.81303dup
LRG_630t1:c.1934dup	LRG_630p1:p.Gly646fs

... more HGVS ... less HGVS

Protein change

G585fs, G646fs

Other names

Canonical SPDI

NC_000020.11:32434638:GGGGGGGG:GGGGGGGGG

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: CA9808490 dbSNP: rs750318549 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.
ASXL1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1016	1038

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.
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 23, 2023	RCV000489373.7
Bohring-Opitz syndrome	Pathogenic/Likely pathogenic (7)	criteria provided, multiple submitters, no conflicts	Mar 25, 2024	RCV000677687.13
Abnormal brain morphology	Likely pathogenic (1)	criteria provided, single submitter	-	RCV001526628.2
ASXL1-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 3, 2024	RCV004740262.1

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 (Aug 22, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bohring-Opitz syndrome Affected status: yes Allele origin: de novo	Baylor Genetics Accession: SCV001526547.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormal brain morphology Affected status: yes Allele origin: de novo	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV001737058.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021
Pathogenic (Dec 18, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bohring-Opitz syndrome Affected status: yes Allele origin: de novo	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001934374.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Comment: This variant was identified as de novo (maternity and paternity confirmed).
Pathogenic (Feb 12, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000577504.4 First in ClinVar: May 22, 2017 Last updated: May 22, 2017	Comment: Frameshift variant predicted to result in protein truncation, as the last 896 amino acids are replaced with 11 different amino acids, and other loss-of-function variants … (more) Frameshift variant predicted to result in protein truncation, as the last 896 amino acids are replaced with 11 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 28832022, 33502020, 32381577, 28229513, 20596031, 20693432, 30013160, 29681105, 30147881) (less)
Pathogenic (May 27, 2021)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV002817241.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Comment: This variant causes a frameshift at codon 646 which results in the creation of a premature stop codon and the loss of 896 amino acids. … (more) This variant causes a frameshift at codon 646 which results in the creation of a premature stop codon and the loss of 896 amino acids. Multiple truncating variants in this region have been reported in patients with Bohring-Opitz syndrome (PMID: 21706002, 28229513). This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene (PMID: 29681105, 30147881). This variant has been observed in the general population at a frequency higher than expected for a pathogenic variant in this gene. However, this frequency may represent acquired somatic mosaicism which has been reported to occur with age during hematopoietic clonal expansion of cells with pathogenic ASXL1 variants in healthy individuals. (https://gnomad.broadinstitute.org/, PMID 28229513)This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. (less)
Pathogenic (Jun 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bohring-Opitz syndrome Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807114.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 moderated, PM6 strong Number of individuals with the variant: 1 Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Likely pathogenic (Mar 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bohring-Opitz syndrome Affected status: yes Allele origin: de novo	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Study: Clinvar_gadteam_Clinical_exome_analysis_3 Accession: SCV000803831.2 First in ClinVar: Aug 25, 2018 Last updated: Mar 26, 2023	Method: Exome sequencing
Pathogenic (Nov 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bohring-Opitz syndrome Affected status: yes Allele origin: de novo	Daryl Scott Lab, Baylor College of Medicine Accession: SCV004102730.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023
Pathogenic (Oct 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bohring-Opitz syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003811056.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Dec 23, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003288802.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 29681105‚ 30147881 Comment: This sequence change creates a premature translational stop signal (p.Gly646Trpfs12) in the ASXL1 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Gly646Trpfs12) in the ASXL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 896 amino acid(s) of the ASXL1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Bohring-Opitz syndrome (PMID: 29681105, 30147881). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 426927). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 25, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Bohring-Opitz syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002500552.4 First in ClinVar: Apr 23, 2022 Last updated: Jun 29, 2024	Publications: PubMed (20) PubMed: 22489043‚ 24442206‚ 24458439‚ 25652455‚ 24695057‚ 23018865‚ 21881046‚ 23619563‚ 20880116‚ 23690417‚ 22031865‚ 25596267‚ 22058207‚ 24496303‚ 21576631‚ 24255920‚ 27895058‚ 27276561‚ 29681105‚ 30147881 Comment: Variant summary: ASXL1 c.1934dupG (p.Gly646TrpfsX12) located in the last exon results in a premature termination codon, predicted to cause a truncation of the encoded protein … (more) Variant summary: ASXL1 c.1934dupG (p.Gly646TrpfsX12) located in the last exon results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in association with Bohring-Opitz syndrome in the HGMD/LOVD databases. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1934dupG has been reported in the literature as a de-novo variant in at-least two individuals affected with Bohring-Opitz Syndrome (example, Kibe_2017, Urreizti_2018). As this variant is located in a homopolymer tract of guanines it is prone to replication slippage and could be overrepresented as sequencing artifacts. This variant has also been reported to be a common cancer-associated ASXL1 variant in settings of myeloid malignancies (Van Ness_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 426927). Based on the evidence outlined above, in settings where somatic mosaicism, clonal hematopoiesis of indeterminate potential (CHIP) and technical artifacts of analysis are ruled out, the variant was classified as pathogenic in association with Bohring-Opitz Syndrome. (less)
Pathogenic (Jul 03, 2024)	no assertion criteria provided Method: clinical testing	ASXL1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005362549.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The ASXL1 c.1934dupG variant is predicted to result in a frameshift and premature protein termination (p.Gly646Trpfs12). This variant has been reported as causative for Bohring-Opitz … (more) The ASXL1 c.1934dupG variant is predicted to result in a frameshift and premature protein termination (p.Gly646Trpfs12). This variant has been reported as causative for Bohring-Opitz syndrome in two patients in the literature (Kibe et al. 2018. PubMed ID: 29681105; Urreizti et al. 2018. PubMed ID: 30147881). It has also been reported as a de novo finding in a patient tested at PreventionGenetics. This variant is present in gnomAD in 0.064% of alleles in individuals of European (Non-Finnish) descent in gnomAD, but it fails data-quality filters, indicative of sequencing errors common to this type of homopolymer (repeat of G nucleotides). Heterozygous frameshift variants in ASXL1 are expected to be pathogenic for autosomal dominant Bohring-Opitz syndrome. This variant is interpreted as pathogenic. (less)
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Comment:

Frameshift variant predicted to result in protein truncation, as the last 896 amino acids are replaced with 11 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 28832022, 33502020, 32381577, 28229513, 20596031, 20693432, 30013160, 29681105, 30147881)

Comment:

This variant causes a frameshift at codon 646 which results in the creation of a premature stop codon and the loss of 896 amino acids. Multiple truncating variants in this region have been reported in patients with Bohring-Opitz syndrome (PMID: 21706002, 28229513). This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene (PMID: 29681105, 30147881). This variant has been observed in the general population at a frequency higher than expected for a pathogenic variant in this gene. However, this frequency may represent acquired somatic mosaicism which has been reported to occur with age during hematopoietic clonal expansion of cells with pathogenic ASXL1 variants in healthy individuals. (https://gnomad.broadinstitute.org/, PMID 28229513)This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.

Comment:

This sequence change creates a premature translational stop signal (p.Gly646Trpfs*12) in the ASXL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 896 amino acid(s) of the ASXL1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Bohring-Opitz syndrome (PMID: 29681105, 30147881). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 426927). For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant summary: ASXL1 c.1934dupG (p.Gly646TrpfsX12) located in the last exon results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in association with Bohring-Opitz syndrome in the HGMD/LOVD databases. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1934dupG has been reported in the literature as a de-novo variant in at-least two individuals affected with Bohring-Opitz Syndrome (example, Kibe_2017, Urreizti_2018). As this variant is located in a homopolymer tract of guanines it is prone to replication slippage and could be overrepresented as sequencing artifacts. This variant has also been reported to be a common cancer-associated ASXL1 variant in settings of myeloid malignancies (Van Ness_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 426927). Based on the evidence outlined above, in settings where somatic mosaicism, clonal hematopoiesis of indeterminate potential (CHIP) and technical artifacts of analysis are ruled out, the variant was classified as pathogenic in association with Bohring-Opitz Syndrome.

Comment:

The ASXL1 c.1934dupG variant is predicted to result in a frameshift and premature protein termination (p.Gly646Trpfs*12). This variant has been reported as causative for Bohring-Opitz syndrome in two patients in the literature (Kibe et al. 2018. PubMed ID: 29681105; Urreizti et al. 2018. PubMed ID: 30147881). It has also been reported as a de novo finding in a patient tested at PreventionGenetics. This variant is present in gnomAD in 0.064% of alleles in individuals of European (Non-Finnish) descent in gnomAD, but it fails data-quality filters, indicative of sequencing errors common to this type of homopolymer (repeat of G nucleotides). Heterozygous frameshift variants in ASXL1 are expected to be pathogenic for autosomal dominant Bohring-Opitz syndrome. This variant is interpreted as pathogenic.

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
The ASXL1 mutation p.Gly646Trpfs*12 found in a Turkish boy with Bohring-Opitz Syndrome.	Urreizti R	Clinical case reports	2018	PMID: 30147881
Lethal persistent pulmonary hypertension of the newborn in Bohring-Opitz syndrome.	Kibe M	American journal of medical genetics. Part A	2018	PMID: 29681105
Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.	Döhner H	Blood	2017	PMID: 27895058
Genomic Classification and Prognosis in Acute Myeloid Leukemia.	Papaemmanuil E	The New England journal of medicine	2016	PMID: 27276561
Integrated genomic profiling, therapy response, and survival in adult acute myelogenous leukemia.	Parkin B	Clinical cancer research : an official journal of the American Association for Cancer Research	2015	PMID: 25652455
ASXL1 mutations in younger adult patients with acute myeloid leukemia: a study by the German-Austrian Acute Myeloid Leukemia Study Group.	Paschka P	Haematologica	2015	PMID: 25596267
ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients.	Patnaik MM	Leukemia	2014	PMID: 24695057
CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients.	Tefferi A	Leukemia	2014	PMID: 24496303
Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study.	Guglielmelli P	Blood	2014	PMID: 24458439
Dynamics of ASXL1 mutation and other associated genetic alterations during disease progression in patients with primary myelodysplastic syndrome.	Chen TC	Blood cancer journal	2014	PMID: 24442206
Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice.	Wang J	Blood	2014	PMID: 24255920
Prognostic score including gene mutations in chronic myelomonocytic leukemia.	Itzykson R	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2013	PMID: 23690417
Mutations and prognosis in primary myelofibrosis.	Vannucchi AM	Leukemia	2013	PMID: 23619563
ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome.	Schnittger S	Leukemia	2013	PMID: 23018865
Mutation analysis of ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 in myeloproliferative neoplasms.	Brecqueville M	Genes, chromosomes & cancer	2012	PMID: 22489043
Acquired mutations in ASXL1 in acute myeloid leukemia: prevalence and prognostic value.	Pratcorona M	Haematologica	2012	PMID: 22058207
ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category.	Metzeler KH	Blood	2011	PMID: 22031865
Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia.	Shen Y	Blood	2011	PMID: 21881046
Prognostic significance of ASXL1 mutations in patients with myelodysplastic syndromes.	Thol F	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2011	PMID: 21576631
ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia.	Gelsi-Boyer V	British journal of haematology	2010	PMID: 20880116
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Text-mined citations for rs750318549 ...

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 13, 2024

ClinVar Genomic variation as it relates to human health

NM_015338.6(ASXL1):c.1934dup (p.Gly646fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs750318549 ...