Submissions for variant NM_182961.4(SYNE1):c.22559G>A (p.Arg7520His) (rs752057121)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000430516	SCV000535843	uncertain significance	not specified	2017-01-05	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SYNE1 gene. The R7449H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R7449H 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 R7449H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties and this substitution occurs at a position that is not conserved. However, 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	RCV001059780	SCV001224426	uncertain significance	Spinocerebellar ataxia, autosomal recessive 8; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2019-02-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 7449 of the SYNE1 protein (p.Arg7449His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs752057121, ExAC 0.001%). This variant has not been reported in the literature in individuals with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 392558). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.