ClinVar Miner

Submissions for variant NM_000100.3(CSTB):c.214_215TC[2] (p.Leu73fs) (rs796943858)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624148 SCV000742064 pathogenic Inborn genetic diseases 2017-05-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Athena Diagnostics Inc RCV000486032 SCV000841998 pathogenic not provided 2018-05-09 criteria provided, single submitter clinical testing
GeneDx RCV000486032 SCV000566780 pathogenic not provided 2015-06-01 criteria provided, single submitter clinical testing The c.218_219delTC deletion in the CSTB gene has been reported previously in association with Unverricht-Lundborg disease (Bespalova et al., 1997; Lafrenière et al., 1997; Lalioti et al., 1997). Additionally, functionalstudies indicate that c.218_219delTC causes markedly reduced levels of cystatin B mRNA compared tounaffected controls (Bespalova et al., 1997; Lalioti et al., 1997). The deletion causes a frameshift starting withcodon Leucine 73, changes this amino acid to a Proline residue and creates a premature Stop codon at position3 of the new reading frame, denoted p.Leu73ProfsX3. This variant is predicted to cause loss of normalprotein function through protein truncation, as the last 26 amino acids of the CSTB protein are lost andreplaced with 2 incorrect amino acids. Therefore, c.218_219delTC is considered a pathogenic variant.
GeneReviews RCV000049369 SCV000195834 pathogenic Unverricht-Lundborg syndrome 2014-11-25 no assertion criteria provided literature only
Invitae RCV000638318 SCV000759812 pathogenic Progressive myoclonic epilepsy 2018-07-19 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the CSTB gene (p.Leu73Profs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acids of the CSTB protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individuals affected with progressive myoclonus epilepsy type 1 (EPM1), however a second variant was not identified in these individuals (PMID:  9012407, 9342192). This variant has been reported in an individual with EPM1 as compound heterozygous with a common pathogenic dodecamer repeat expansion(c.-210CCCCGCCCCGCG(2_3)) in the promotor of CSTB gene (PMID: 9054946). This variant is also known as c.313_314del2, del2399TC, 2404ΔTC in the literature. ClinVar contains an entry for this variant (Variation ID: 55960). Experimental evidence shows that this variant results in loss of CSTB mRNA derived from patient lymphoblastoid cells suggesting it is subject to NMD (PMID: 9342192). In addition, experiments using transfection into cultured cell lines shows this variant results in mislocalized CSTB protein compared to wild type protein (PMID: 15483648, 17920138). CSTB protein functions as a protease inhibitor that regulates intracellular protein degradation and codon 73 in the second hairpin loop of CSTB protein is thought to be a key contact residue for protease binding.  Experimental evidence shows that substitution of leucine at codon 73 with glycine reside results in reduced affinity for cysteine proteases (PMID: 10441148). This suggests that the leucine residue is critical for CSTB protein function and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049369 SCV000081802 probable-pathogenic Unverricht-Lundborg syndrome no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000049369 SCV000538020 likely pathogenic Unverricht-Lundborg syndrome 2016-01-27 criteria provided, single submitter clinical testing The c.218_219delTC (p.Leu73Profs*3) frameshift variant in the CSTB gene has been previously reported as heterozygous in three affected individuals with autosomal recessive Myoclonic epilepsy of Unverricht and Lundborg (Bespalova et al., 1997; Lafrenière et al., 1997; Lalioti et al., 1997). This frameshift variant is predicted to cause a protein termination in exon 3 (out of a total of 3 exons in the coding sequence). The C-terminal end of the protein, which is truncated by this variant, is important for normal protein function (Pol and Bjork, 1999). Nonsense mutations in the CSTB gene have been reported as pathogenic (Gln47*, Arg68*), and thus, loss of function is a known mechanism of disease. Additionally, in vitro functional studies have shown this variant leads to abnormal localization of the protein within the cell, similar to other pathogenic variants (Cipollini et al., 2008; Alakurtti et al., 2005). This c.218_219delTC has been reported at low frequency in the population databases (Exome Sequencing Project [ESP] = NA, 1000 Genomes = NA, and ExAC = 0.001%) and is predicted to be located in an evolutionarily conserved region (GERP = 5.46). Therefore, this collective evidence supports the classification of the c.218_219delTC (p.Leu73Profs*3) as a recessive Likely Pathogenic variant for Myoclonic epilepsy of Unverricht and Lundborg.

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