Submissions for variant NM_182961.4(SYNE1):c.16850G>A (p.Arg5617Gln) (rs141550859)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000724742	SCV000232869	uncertain significance	not provided	2018-08-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000724742	SCV000536357	uncertain significance	not provided	2017-01-25	criteria provided, single submitter	clinical testing	The R5546Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R5546Q variant is observed in 13/10390 (0.13%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae	RCV000699768	SCV000828493	uncertain significance	Spinocerebellar ataxia, autosomal recessive 8; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2019-07-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 5546 of the SYNE1 protein (p.Arg5546Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs141550859, ExAC 0.1%). This variant has not been reported in the literature in individuals with SYNE1-related disease. ClinVar contains an entry for this variant (Variation ID: 198969). 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 glutamine 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.

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