Submissions for variant NM_182961.4(SYNE1):c.25119+1G>A

dbSNP: rs1164612098

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000730578	SCV000858326	pathogenic	not provided	2017-12-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779495	SCV000916128	uncertain significance	SYNE1-related disorder	2017-10-18	criteria provided, single submitter	clinical testing	The SYNE1 c.24975+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for SYNE1-related disorders.
Athena Diagnostics	RCV000730578	SCV004229280	pathogenic	not provided	2023-03-23	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 spinocerebellar ataxia.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005209522	SCV005850647	likely pathogenic	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2024-09-03	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 138 of the SYNE1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 595117). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.