ClinVar Miner

Submissions for variant NM_182961.4(SYNE1):c.15918-12A>G

gnomAD frequency: 0.00004  dbSNP: rs606231134
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000423940 SCV000517245 pathogenic not provided 2022-08-30 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 17159980, 17503513, 33397523)
Eurofins Ntd Llc (ga) RCV000423940 SCV000706697 pathogenic not provided 2017-03-06 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000763141 SCV000893701 pathogenic Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant 2018-10-31 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000423940 SCV002018913 pathogenic not provided 2023-06-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003330382 SCV004038451 pathogenic Emery-Dreifuss muscular dystrophy 4, autosomal dominant 2023-08-08 criteria provided, single submitter clinical testing Variant summary: SYNE1 c.15705-12A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes or weakens the canonical 3' acceptor site and four predict the variant creates a new 3' acceptor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing through the use of a newly created 3' acceptor site which results in the inclusion of intronic material, creating a premature termination codon (Gros-Louis_2007). The variant allele was found at a frequency of 3.2e-05 in 251248 control chromosomes (gnomAD). c.15705-12A>G has been reported in the literature as a biallelic genotype in many French-Canadian individuals from multiple families affected with autosomal recessive cerebellar ataxia type 1 (ARCA1) (e.g. Gros-Louis_2007, Haj Salem_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17159980, 33397523). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000002416 SCV000022574 pathogenic Autosomal recessive ataxia, Beauce type 2007-07-01 no assertion criteria provided literature only

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