Submissions for variant NM_182961.4(SYNE1):c.17848G>C (p.Val5950Leu) (rs200589166)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000516625	SCV000615588	uncertain significance	not specified	2017-06-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000767056	SCV000620646	uncertain significance	not provided	2017-09-08	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SYNE1 gene. The V5879L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V5879Lvariant is observed in 2/10406 (0.02%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the V5879L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000686323	SCV000813837	uncertain significance	Spinocerebellar ataxia, autosomal recessive 8; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2018-05-26	criteria provided, single submitter	clinical testing	This sequence change replaces valine with leucine at codon 5879 of the SYNE1 protein (p.Val5879Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs200589166, ExAC 0.02%). This variant has not been reported in the literature in individuals with SYNE1-related disease. ClinVar contains an entry for this variant (Variation ID: 448564). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000767056	SCV001154924	uncertain significance	not provided	2018-12-01	criteria provided, single submitter	clinical testing