Submissions for variant NM_182961.4(SYNE1):c.13435C>T (p.Arg4479Cys) (rs778601377)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000726500	SCV000345085	uncertain significance	not provided	2016-09-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000726500	SCV000536596	uncertain significance	not provided	2017-01-26	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SYNE1 gene. The R4408C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R4408C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R4408C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000799265	SCV000938919	uncertain significance	Spinocerebellar ataxia, autosomal recessive 8; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2019-06-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 4408 of the SYNE1 protein (p.Arg4408Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs778601377, ExAC 0.02%). This variant has not been reported in the literature in individuals with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 290514). 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.