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

dbSNP: rs750318549

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489373	SCV000577504	pathogenic	not provided	2021-02-12	criteria provided, single submitter	clinical testing	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)
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000677687	SCV000803831	likely pathogenic	Bohring-Opitz syndrome	2021-03-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000677687	SCV001526547	pathogenic	Bohring-Opitz syndrome	2018-08-22	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001526628	SCV001737058	likely pathogenic	Abnormal brain morphology		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000677687	SCV001934374	pathogenic	Bohring-Opitz syndrome	2020-12-18	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000677687	SCV002500552	pathogenic	Bohring-Opitz syndrome	2024-03-25	criteria provided, single submitter	clinical testing	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.
Athena Diagnostics	RCV000489373	SCV002817241	pathogenic	not provided	2021-05-27	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000489373	SCV003288802	pathogenic	not provided	2023-12-23	criteria provided, single submitter	clinical testing	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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000677687	SCV003807114	pathogenic	Bohring-Opitz syndrome	2022-06-14	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 moderated, PM6 strong
Revvity Omics, Revvity	RCV000677687	SCV003811056	pathogenic	Bohring-Opitz syndrome	2022-10-03	criteria provided, single submitter	clinical testing
Daryl Scott Lab, Baylor College of Medicine	RCV000677687	SCV004102730	pathogenic	Bohring-Opitz syndrome	2023-11-10	criteria provided, single submitter	clinical testing