ClinVar Miner

Submissions for variant NM_182961.4(SYNE1):c.16390-2A>G (rs759460806)

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Total submissions: 4
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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.
Athena Diagnostics Inc RCV000993140 SCV001145900 pathogenic not provided 2018-10-18 criteria provided, single submitter clinical testing The variant disrupts a canonical splice site, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Ambry Genetics RCV001265815 SCV001443987 pathogenic Inborn genetic diseases 2018-03-09 criteria provided, single submitter clinical testing
OMIM RCV000002415 SCV000022573 pathogenic Spinocerebellar ataxia, autosomal recessive 8 2007-01-01 no assertion criteria provided literature only

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