ClinVar Miner

Submissions for variant NM_000100.3(CSTB):c.67-1G>C (rs147484110)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622443 SCV000742065 likely pathogenic Inborn genetic diseases 2016-01-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Athena Diagnostics Inc RCV000187278 SCV000613026 pathogenic not provided 2016-12-15 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000187278 SCV000335378 pathogenic not provided 2015-09-15 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000008903 SCV000893558 pathogenic Unverricht-Lundborg syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000187278 SCV000240860 pathogenic not provided 2018-11-06 criteria provided, single submitter clinical testing The c.67-1 G>C site variant in the CSTB gene has been previously reported in association with Unverricht-Lundborg disease in patients who harbored a second disease-causing variants on the other allele (Pennacchio et al., 1996; Canafoglia et al., 2012). This variant destroys the canonical splice acceptor site in intron 1. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.67-1 G>C variant is observed in 46/277200 (0.017%) alleles in large population cohorts, with no homozygotes observed (Lek et al., 2016). We interpret c.67-1 G>C as a pathogenic variant.
GeneReviews RCV000008903 SCV000195824 pathogenic Unverricht-Lundborg syndrome 2014-11-25 no assertion criteria provided literature only
Genetic Services Laboratory, University of Chicago RCV000194700 SCV000247125 pathogenic Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 2014-12-06 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000008903 SCV000328698 pathogenic Unverricht-Lundborg syndrome 2016-10-13 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000008903 SCV000915956 pathogenic Unverricht-Lundborg syndrome 2018-08-31 criteria provided, single submitter clinical testing The CSTB c.67-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. Across a selection of the literature, the c.67-1G>C variant has been identified in a compound heterozygous state in at least seven individuals with Unverricht-Lundborg disease (ULD) from six families and in one additional family where zygosity was not specified (Pennacchio et al. 1996; Joensuu et al. 2007 and Canafoglia et al. 2012). The c.67-1G>C variant was most commonly identified in a compound heterozygous state with the expanded dodecamer repeat variant, which is the most common pathogenic variant associated with ULD. Bespalova et al. (1997) analyzed mRNA transcripts from heterozygous individuals carrying the c.67-1G>C variant. RT-PCR of total mRNA showed an aberrant, shorter transcript created as a result of skipping of exon 2, confirming that the c.67-1G>C variant disrupts normal splicing and results in expression of a truncated protein. The c.67-1G>C variant was absent from at least 95 unaffected control individuals and is reported at a frequency of 0.000347 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the c.67-1G>C variant is classified as pathogenic for Unverricht-Lundborg disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000638304 SCV000759798 pathogenic Progressive myoclonic epilepsy 2018-05-23 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 1 of the CSTB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs147484110, ExAC 0.02%). This variant has been reported in individuals affected with Unverricht-Lundborg disease (PMID: 8596935, 9012407, 9054946, 23205931). It is also known as 1924G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 8395). Experimental studies have shown that this variant results decreased levels of mRNA and a lack of protein expression, perhaps due to skipping of exon 2 (PMID: 9360639, 17003839). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000008903 SCV000029113 pathogenic Unverricht-Lundborg syndrome 1996-03-22 no assertion criteria provided literature only

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