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

dbSNP: rs759460806

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2020-11-20	criteria provided, single submitter	clinical testing	This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene.
Ambry Genetics	RCV001265815	SCV001443987	pathogenic	Inborn genetic diseases	2018-03-09	criteria provided, single submitter	clinical testing
Invitae	RCV001383383	SCV001582513	pathogenic	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2020-08-03	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 84 of the SYNE1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with cerebellar ataxia (PMID: 17159980, 31103315). ClinVar contains an entry for this variant (Variation ID: 667389). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 17159980). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SYNE1 are known to be pathogenic (PMID: 19542096, 24319099, 27086870). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000993140	SCV002018910	pathogenic	not provided	2019-03-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000993140	SCV002817828	pathogenic	not provided	2022-12-27	criteria provided, single submitter	clinical testing	Reported with a second variant in the SYNE1 gene in patients with ataxia in the literature; however, segregation information and/or information about the second variant was not provided for all cases (Gros-Louis et al., 2007; Haj Salem et al., 2021); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17159980, 25525159, 27782104, 25843669, 31103315, 33397523)
OMIM	RCV000002415	SCV000022573	pathogenic	Autosomal recessive ataxia, Beauce type	2007-01-01	no assertion criteria provided	literature only