Submissions for variant NM_182961.4(SYNE1):c.18091G>A (p.Glu6031Lys)

gnomAD frequency: 0.00024  dbSNP: rs142229551

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000290216	SCV000461071	uncertain significance	Autosomal recessive ataxia, Beauce type	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory 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, this variant 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, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000344274	SCV000461072	likely benign	Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698873	SCV000827562	uncertain significance	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2024-05-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 5960 of the SYNE1 protein (p.Glu5960Lys). This variant is present in population databases (rs142229551, gnomAD 0.07%). This missense change has been observed in individual(s) with cerebellar ataxia, congenital cerebellar hypoplasia, and cognitive impairment (PMID: 30275942). ClinVar contains an entry for this variant (Variation ID: 355850). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Eurofins Ntd Llc (ga)	RCV000734241	SCV000862365	uncertain significance	not provided	2018-07-12	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000734241	SCV001476993	uncertain significance	not provided	2020-09-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000734241	SCV003824698	uncertain significance	not provided	2020-06-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000734241	SCV004034348	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing	Observed with another variant on the opposite allele (in trans) in monozygotic twins with childhood-onset ataxia, cerebellar hypoplasia, hypotonia, and cognitive impairment (PMID: 30275942); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30275942)
PreventionGenetics, part of Exact Sciences	RCV004544670	SCV004771045	uncertain significance	SYNE1-related disorder	2024-02-21	no assertion criteria provided	clinical testing	The SYNE1 c.17878G>A variant is predicted to result in the amino acid substitution p.Glu5960Lys. This variant was reported in the compound heterozygous state in monozygotic twins with cerebellar ataxia, congenital cerebellar hypoplasia and cognitive impairment (Swan et al. 2018. PubMed ID: 30275942). This variant is reported in 0.068% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.