Submissions for variant NM_014233.4(UBTF):c.628G>A (p.Glu210Lys)

dbSNP: rs1555582065

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mark LeDoux Lab, University of Tennessee Health Science Center	RCV000504592	SCV000598648	pathogenic	UBTF E210K Neuroregression Syndrome	2017-09-02	criteria provided, single submitter	clinical testing	Patient fibroblasts showed normal levels of UBTF transcript, increased expression of pre-rRNA and 18S rRNA, nucleolar abnormalities, markedly increased numbers of DNA breaks, defective cell-cycle progression, and apoptosis. Expression of mutant human UBTF NM_014233.3:c.628G>A cDNA in Drosophila neurons was lethal.
Undiagnosed Diseases Program Translational Research Laboratory, National Institutes of Health	RCV000625527	SCV000599454	likely pathogenic	Infantile or childhood onset neurodegenerative disease, global developmental delay, and intellectual disability	2017-09-11	criteria provided, single submitter	research	We have 3 patients with similar clinical phenotype, not otherwise associated with other genes, shown to harbor this particular variant that was found by exome sequencing.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000505522	SCV000680424	pathogenic	Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder	2017-12-11	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000505522	SCV000787458	likely pathogenic	Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder	2018-04-16	criteria provided, single submitter	curation	This variant is interpreted as a Likely Pathogenic, for Neurodegeneration, childhood-onset, with brain atrophy, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:28777933). PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:28777933).
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000505522	SCV001251914	pathogenic	Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder	2020-05-03	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195293	SCV001365605	pathogenic	Rare syndromic intellectual disability	2020-03-04	criteria provided, single submitter	clinical testing	The p.Glu210Lys variant in UBTF has been reported as a de novo occurrence, with maternity and paternity confirmed, in at least 10 individuals with clinical features of neurodegeneration in childhood (Edvardson et al 2017; Kosmicki et al 2017; Sedlackova et al 2018; Toro et al 2018; Bastos et al 2020). This variant has been reported in ClinVar (Variation ID: 437909) and was absent from large population studies. In vitro functional studies provide evidence that the p.Glu210Lys variant impacts protein function (PMID: 28777933, 29300972). However, these types of assays may not accurately represent biological function. Additionally, computational prediction tools and conservation analysis suggest that the p.Glu210Lys variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for neurodegeneration in childhood in an autosomal dominant manner based upon de novo inheritance in multiple cases and absence from controls. ACMG/AMP Criteria applied: PS2_VeryStrong, PS4, PM2, PS3_Moderate, PP3.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000505522	SCV001430727	pathogenic	Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder	2020-05-27	criteria provided, single submitter	research	The heterozygous p.Glu210Lys variant in UBTF was identified by our study in 2 unrelated individuals with childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder. Trio exome or genome analysis showed this variant to be de novo. This variant was found to be de novo in an additional individual with confirmed paternity and maternity and neurodegeneration in childhood (PMID: 30517966). This variant is assumed de novo in at least 11 additional individuals, 10 with neurodegeneration in childhood and 1 with either intellectual disability or developmental delay, but maternity and paternity have not been confirmed (PMID: 28191890, 29300972, 28777933). This variant was absent from large population studies. Additionally, this variant has also been reported as pathogenic and likely pathogenic by multiple submitters in ClinVar (Variation ID: 437909). Animal models in drosophilia and mice have shown that this variant may cause childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder (PMID: 29300972). Furthermore, in vitro functional studies provide some evidence that the p.Glu210Lys variant may impact protein function (PMID: 28777933, 29300972). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder in an autosomal dominant manner based on multiple de novo reports in affected individuals and functional studies. ACMG/AMP Criteria applied: PM6_Strong, PS2, PM2, PS3_Moderate, PS4_moderate (Richards 2015).
Ambry Genetics	RCV001265907	SCV001444079	pathogenic	Inborn genetic diseases	2017-05-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000505522	SCV001523961	pathogenic	Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder	2020-02-07	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000505522	SCV001571368	pathogenic	Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder	2021-04-13	criteria provided, single submitter	clinical testing
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli	RCV001420236	SCV001622656	pathogenic	See cases	2021-04-26	criteria provided, single submitter	clinical testing	PP5_very strong;PM1_moderate;PM2_supporting;PM6_moderate;PP2_supporting;PP3_supporting
Illumina Laboratory Services, Illumina	RCV000505522	SCV001786624	pathogenic	Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder	2020-11-16	criteria provided, single submitter	clinical testing	The UBTF c.628G>A (p.Glu210Lys) variant is a missense variant that has been reported in 14 unrelated individuals with childhood-onset neurodegeneration (Edvardson et al. 2017; Toro et al. 2018; Sedláčková et al. 2019; Ikeda et al. 2020; Bastos et al. 2020). In all cases, the variant occurred de novo. The p.Glu210Lys variant is absent from the Genome Aggregation Database in a region of good sequencing coverage, indicating it is rare. Studies of patient fibroblasts have suggested a gain-of-function effect of the variant, demonstrating increased expression of pre-rRNA and 18S rRNA, altered expression levels of downstream gene targets, increased double-strand DNA breaks, disrupted cell cycle progression and increased apoptosis, and at least a trend toward fewer nucleoli (Edvardson et al. 2017, Toro et al. 2018). Expression of the variant in Drosophila also resulted in embryonic lethality (Toro et al. 2018). Based on the collective evidence, the p.Glu210Lys variant is classified as pathogenic for childhood-onset neurodegeneration with brain atrophy.
GeneDx	RCV001566123	SCV001789596	pathogenic	not provided	2023-06-08	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23020937, 29300972, 28777933, 30517966, 31931739, 28191890, 29447355, 33084218, 33026538, 33726816, 31785789, 33101984)
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV000505522	SCV002559201	pathogenic	Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000505522	SCV002766994	pathogenic	Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with neurodegeneration, childhood-onset, with brain atrophy (MIM# 617672). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and identified as a recurrent de novo variant in greater than ten individuals in the literature (PMID: 29300972, PMID: 28777933). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Patient fibroblasts showed increased expression of pre-rRNA and 18S rRNA, as well as nucleolar abnormalities (PMID: 29300972). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000505522	SCV003807240	pathogenic	Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder	2022-11-18	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 very strong
3billion	RCV000505522	SCV003841269	pathogenic	Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.68). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000437909). The variant has been previously reported as de novo in a similarly affected individual (PMID: 28777933). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV000505522	SCV004238390	pathogenic	Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder	2023-06-26	criteria provided, single submitter	clinical testing
OMIM	RCV000505522	SCV000599783	pathogenic	Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder	2018-08-31	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000845031	SCV000986866	not provided	UBTF-related disorder		no assertion provided	phenotyping only	Variant interpretted as pathogenic and reported on 09/21/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.