Submissions for variant NM_182914.3(SYNE2):c.17583G>T (p.Trp5861Cys)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002472233	SCV002769332	uncertain significance	Emery-Dreifuss muscular dystrophy 5, autosomal dominant	2020-05-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. 0104 - Mechanism of disease for this gene is dominant negative. 0107 - This gene is known to be associated with autosomal dominant disease. 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to cysteine (exon 97). 0301 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). 0501 - Missense variant consistently predicted to be damaging by in-silico tools or highly conserved with a major amino acid change. 0600 - Variant is located in an annotated domain or motif that does not have a well established function (SMC prok B superfamily domain; NCBI). 0705 - No comparable variants in relevant codon/region have previous evidence for pathogenicity. 0807 - Variant has not previously been reported in a clinical context. 0905 - No published segregation evidence has been identified for this variant. 1007 - No published functional evidence has been identified for this variant. 1205 - Variant is maternally inherited. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV002472233	SCV004622660	uncertain significance	Emery-Dreifuss muscular dystrophy 5, autosomal dominant	2023-02-15	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 5861 of the SYNE2 protein (p.Trp5861Cys). This variant is present in population databases (rs767570119, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SYNE2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1805815). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.