ClinVar Genomic variation as it relates to human health

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.

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).

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.

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).

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.

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

PP5_very strong;PM1_moderate;PM2_supporting;PM6_moderate;PP2_supporting;PP3_supporting

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.

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

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 very strong

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.

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)

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.