Submissions for variant NM_030632.3(ASXL3):c.5467C>T (p.Arg1823Ter)

dbSNP: rs2145432318

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002267256	SCV002549263	pathogenic	not provided	2024-04-11	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 426 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: 33004838, 30564305)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471271	SCV002767537	pathogenic	Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome	2020-05-25	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 12 of 12). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0401 - Variant is located in a gene associated with a severe early-onset dominant condition that is intolerant to loss-of-function variants. (P) 0601 - Variant affects at least one functional domain or motif (PHD domain). While no functional studies have been done in ASXL3, the PHD domain in ASXL2 has been shown to bind to H3K4me2 histone tail (PMID: 26640146 ) (P) 0702 - Comparable downstream truncating variants have previous evidence for pathogenicity. (ClinVar, DECIPHER, PMID: 29628764) (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. De novo in an patient with autism spectrum disorder (PMID: 30564305) (P) 0905 - No segregation evidence has been identified for this variant, ie. no segregation studies published in literature. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002471271	SCV003923212	likely pathogenic	Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome	2023-03-28	criteria provided, single submitter	clinical testing	Variant summary: ASXL3 c.5467C>T (p.Arg1823X) 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 ASXL3-related syndrome (HGMD database and Verhoeven_2018). The variant was absent in 249170 control chromosomes. c.5467C>T has been reported in the literature as a de-novo variant in at-least one individual affected with Autism Spectrum Disorder (ASD) (example, Guo_2018 with patient overlap in Wang_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.