ClinVar Miner

Submissions for variant NM_033071.3(SYNE1):c.16177-2A>G

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826129 SCV000967643 likely pathogenic Autosomal recessive cerebellar ataxia 2019-01-11 criteria provided, single submitter clinical testing The c.16390-2A>G variant in SYNE1 has been reported in the compound heterozygous state in 2 French-Canadian families with autosomal recessive cerebellar ataxia (Gros-Louis 2007). Although the variant was reported to segregate with disease i n affected family members, it is unclear how many individuals were tested. The c .16390-2A>G variant has also been identified in 0.001% (1/113116) of European ch romosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs with in the canonical splice site (+/- 1,2) and functional studies demonstrate that i t results in the insertion of single nucleotide, which is then predicted to caus e a frameshift leading to a truncated or absent protein (Gros-Louis 2007). Altho ugh, the variant falls within an alternatively spliced exon of the SYNE1 gene, i soforms containing this exon are expressed in the cerebellum (Razafsky 2015; GTE x, https://gtexportal.org). Loss of function of the SYNE1 gene is an established disease mechanism in autosomal recessive cerebellar ataxia. In summary, althoug h additional studies are required to fully establish its clinical significance, the c.16390-2A>G variant meets criteria to be classified as likely pathogenic fo r autosomal recessive cerebellar ataxia. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PP1, PM3_Supporting.
OMIM RCV000002415 SCV000022573 pathogenic Spinocerebellar ataxia, autosomal recessive 8 2007-01-01 no assertion criteria provided literature only

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