ClinVar Miner

Submissions for variant NM_182961.4(SYNE1):c.20072G>A (p.Trp6691Ter) (rs766499430)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000779500 SCV000916133 uncertain significance SYNE1-Related Disorders 2018-12-10 criteria provided, single submitter clinical testing The SYNE1 c.19859G>A (p.Trp6620Ter) stop-gained variant has been reported in a compound heterozygous state in three affected siblings and in a heterozygous state in three unaffected siblings in a French Canadian family (Noreau et al. 2013). The age of onset in the affected individuals was around age 30 and clinical features were consistent with cerebellar ataxia, including dysarthria, gait ataxia, and abnormal eye movements. The p.Trp6620Ter variant was absent from 196 healthy control individuals and is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of stop-gained variants and the limited clinical evidence, the p.Trp6620Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for SYNE1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001216663 SCV001388470 pathogenic Spinocerebellar ataxia, autosomal recessive 8; Emery-Dreifuss muscular dystrophy 4, autosomal dominant 2019-08-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp6620*) in the SYNE1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs766499430, ExAC 0.002%). This variant has been observed to segregate with autosomal recessive spinocerebellar ataxia in a family (PMID: 23959263). ClinVar contains an entry for this variant (Variation ID: 632480). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in SYNE1 are known to be pathogenic (PMID: 27086870). For these reasons, this variant has been classified as Pathogenic.

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