ClinVar Miner

Submissions for variant NM_014233.4(UBTF):c.628G>A (p.Glu210Lys) (rs1555582065)

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Total submissions: 13
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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, Klinikum rechts der Isar 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,Partners HealthCare 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 Institute Rare Disease Group, Broad Institute 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
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.

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