Submissions for variant NM_182961.4(SYNE1):c.21782G>A (p.Arg7261Gln) (rs61742716)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726696	SCV000590327	uncertain significance	not provided	2017-06-14	criteria provided, single submitter	clinical testing	The R7190Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R7190Q variant is observed in 7/10406 (0.07%) 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 is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Athena Diagnostics Inc	RCV000497411	SCV000615614	uncertain significance	not specified	2017-03-13	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000726696	SCV000702180	uncertain significance	not provided	2016-10-04	criteria provided, single submitter	clinical testing
Invitae	RCV000801869	SCV000941667	uncertain significance	Spinocerebellar ataxia, autosomal recessive 8; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2018-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 7190 of the SYNE1 protein (p.Arg7190Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs61742716, ExAC 0.07%). This variant has not been reported in the literature in individuals with SYNE1-related disease. ClinVar contains an entry for this variant (Variation ID: 432582). 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.