Submissions for variant NM_182961.4(SYNE1):c.3504+5G>A

gnomAD frequency: 0.00001  dbSNP: rs1398879746

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002038148	SCV002293804	uncertain significance	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2022-06-27	criteria provided, single submitter	clinical testing	This sequence change falls in intron 28 of the SYNE1 gene. It does not directly change the encoded amino acid sequence of the SYNE1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004785451	SCV005400283	uncertain significance	Autosomal recessive ataxia, Beauce type	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive spinocerebellar ataxia 8 (MIM#610743). (I) 0108 - This gene is associated with both recessive and dominant disease. Heterozygous variants result in Emery-Dreifuss muscular dystrophy 4 (MIM#612998), whereas biallelic variants can cause either myogenic type arthrogryposis multiplex congenita 3 (MIM#618484) or spinocerebellar ataxia 8 (MIM#610743). Variants causing arthrogryposis typically truncate the C-terminal KASH domain in the muscle-specific isoform, whereas spinocerebellar ataxia variants affect the larger isoform (OMIM). (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 2 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0710 - Another splice variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The variant c.3504+5G>C has been reported as a VUS in ClinVar. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I)