Submissions for variant NM_000100.4(CSTB):c.218_219del (p.Leu73fs)

dbSNP: rs796943858

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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.
GeneDx	RCV000486032	SCV000566780	likely pathogenic	not provided	2024-02-12	criteria provided, single submitter	clinical testing	Published functional studies suggest that the variant does not localize to lysosomes as compared to unaffected controls (PMID: 15483648, 17920138); Frameshift variant predicted to result in protein truncation as the last 26 amino acids are replaced with 2 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9054946, 9342192, 7543407, 17003839, 30669344, 17920138, 31440721, 38247861, 9012407, 15483648)
Ambry Genetics	RCV000624148	SCV000742064	pathogenic	Inborn genetic diseases	2022-02-28	criteria provided, single submitter	clinical testing	The c.218_219delTC (p.L73Pfs*3) alteration, located in exon 3 (coding exon 3) of the CSTB gene, consists of a deletion of 2 nucleotides from position 218 to 219, causing a translational frameshift with a predicted alternate stop codon after 3 amino acids. This alteration occurs at the 3' terminus of the CSTB gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 26 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function. Based on data from gnomAD, this allele has an overall frequency of 0.003% (7/282872) total alleles studied. The highest observed frequency was 0.005% (6/129176) of European (non-Finnish) alleles. This mutation has been reported in three unrelated individuals with Unverricht-Lundborg disease (EPM1) (Bespalova, 1997; Lafrenière, 1997; Lalioti, 1997). A second mutation (expansion of the dodecamer repeat) was identified in one of the individuals. Studies of bovine CSTB have shown that some of the C-terminal residues affected by this truncation are important for protein function (Pol, 1999). In addition, this protein truncation is predicted to be structurally destabilizing and to disrupt binding of target proteins (Ambry internal data; Stubbs, 1990; Jenko Kokalj, 2007). Functional analysis demonstrated that levels of CSTB mRNA were significantly decreased in cells from patients heterozygous for the CSTB c.218_219delTC (p.L73Pfs*3) alteration compared to unaffected individuals (Lafrenière, 1997; Bespalova, 1997). When the L73Pfs*3 protein was expressed in vitro, the mutant protein had diffuse distribution in the cytoplasm and nucleus and did not colocalize with lysosomes (Alakurtti, 2005). Based on the available evidence, this alteration is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000638318	SCV000759812	pathogenic	Progressive myoclonic epilepsy	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu73Profs*3) in the CSTB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acid(s) of the CSTB protein. This variant is present in population databases (rs796943858, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with progressive myoclonus epilepsy type 1 (PMID: 9012407, 9054946, 9342192). This variant is also known as c.313_314del2, del2399TC, and 2404ΔTC. ClinVar contains an entry for this variant (Variation ID: 55960). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CSTB function (PMID: 9342192, 15483648, 17920138). This variant disrupts the p.Leu73 amino acid residue in CSTB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10441148). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000486032	SCV000841998	pathogenic	not provided	2024-09-16	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 at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049369	SCV002598543	pathogenic	Unverricht-Lundborg syndrome	2022-09-30	criteria provided, single submitter	clinical testing	Variant summary: CSTB c.218_219delTC (p.Leu73ProfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.5e-05 in 282872 control chromosomes (gnomAD). c.218_219delTC has been reported in the literature in individuals affected with Unverricht-Lundborg Syndrome (e.g. Lafreniere_1997, Lalioti_1997, Bespalova_1997). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating protein function, and found that the variant does not localize to the lysosomes which may contribute to misfunction (Alakurtti_2005). Five ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and four as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000049369	SCV003819362	pathogenic	Unverricht-Lundborg syndrome	2021-11-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000486032	SCV004225371	pathogenic	not provided	2023-03-31	criteria provided, single submitter	clinical testing	PP4, PM2, PS3, PS4_moderate, PVS1_strong
OMIM	RCV000049369	SCV000029117	pathogenic	Unverricht-Lundborg syndrome	2005-02-01	no assertion criteria provided	literature only
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.
GeneReviews	RCV000049369	SCV000195834	not provided	Unverricht-Lundborg syndrome		no assertion provided	literature only