Submissions for variant NM_000100.4(CSTB):c.202C>T (p.Arg68Ter)

gnomAD frequency: 0.00001  dbSNP: rs74315442

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000008904	SCV000436264	pathogenic	Unverricht-Lundborg syndrome	2016-06-14	criteria provided, single submitter	clinical testing	The c.202C>T (p.Arg68Ter) variant has been reported in at least five studies in which it is found in a total of 11 Unverricht-Lundborg disease patients, including two affected siblings in a homozygous state, seven patients in a compound heterozygous state (including two sibling pairs), and in two patient alleles where zygosity was not specified (Pennacchio et al. 1996; Lafrenière et al. 1997; de Haan et al. 2004; Koskenkorva et al. 2010; Mancini et al. 2016). The p.Arg68Ter variant was absent from 377 controls but is reported at a frequency of 0.00006 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Functional analyses demonstrated that the variant resulted in reduced cell viability by 26% compared to wild-type in transfected CHO-K1 cells (Ceru et al. 2010). Additionally, the p.Arg68Ter variant protein did not localize to the nucleus. The variant produced an unfolded protein leading to protein aggregation which resulted in perinuclear aggregates that were more pronounced than wild type (Rabzelj et al. 2005; Ceru et al. 2010; Polajnar et al. 2012). Based on the evidence and the potential impact of stop-gained variants, the p.Arg68Ter variant is classified as pathogenic for Unverricht-Lundborg disease.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626611	SCV000747312	pathogenic	Dystonic disorder; Motor delay; Aplasia/Hypoplasia of the corpus callosum; Dyskinesia; Progressive microcephaly; Global brain atrophy; Intellectual disability, severe; Severe global developmental delay	2017-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387303	SCV001587897	pathogenic	Progressive myoclonic epilepsy	2022-03-08	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CSTB protein in which other variant(s) (p.Leu73Profs*3) have been determined to be pathogenic (PMID: 9054946, 9342192, 15483648, 17920138). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this premature translational stop signal affects CSTB function (PMID: 15483648). ClinVar contains an entry for this variant (Variation ID: 8396). This premature translational stop signal has been observed in individual(s) with progressive myoclonus epilepsy (PMID: 8596935, 26843564). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs74315442, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Arg68*) in the CSTB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the CSTB protein.
Athena Diagnostics	RCV002472925	SCV002771348	pathogenic	not provided	2022-06-17	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with progressive myoclonic epilepsy. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant leads to the formation of protein aggregates (PMID: 17920138, 20078424)
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000008904	SCV005045045	pathogenic	Unverricht-Lundborg syndrome	2024-01-25	criteria provided, single submitter	clinical testing	The CSTB c.202C>T (p.Arg68Ter) variant has been reported in over 10 patients with Unverricht-Lundborg syndrome and is reported to segregate with disease in six individuals in three families (Koskenkorva P et al., PMID: 21757863; Lafreniere RG et al., PMID: 9054946; Mancini GM et al., PMID: 26843564, Pennacchio LA et al., PMID: 8596935). Of those individuals, two siblings were homozygous for the variant (Mancini GM et al., PMID: 26843564) and seven were compound heterozygous for the variant and a pathogenic repeat expansion confirmed in trans (Koskenkorva P et al., PMID: 21757863). This variant leads to a premature termination codon; however, because this occurs in the last exon, this is not predicted to lead to nonsense mediated decay. It does disrupt the last 31 amino acids of the CSTB protein. Functional studies show protein aggregation in the perinuclear region and reduced cell viability compared to wild type, indicating that this variant impacts protein function (Ceru S et al., PMID: 20078424; Rabzelj S et al., PMID: 16155205). This variant is only observed on 13 out of 282,868 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant has been reported in the ClinVar database as a germline pathogenic variant by five submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
OMIM	RCV000008904	SCV000029114	pathogenic	Unverricht-Lundborg syndrome	2005-02-01	no assertion criteria provided	literature only
GeneReviews	RCV000008904	SCV000195832	not provided	Unverricht-Lundborg syndrome		no assertion provided	literature only
Bioinformatics Core, Luxembourg Center for Systems Biomedicine	RCV000656065	SCV000588341	pathogenic	Self-limited epilepsy with centrotemporal spikes	2017-01-01	no assertion criteria provided	case-control	CAADphred>15