Submissions for variant NM_182914.3(SYNE2):c.1243G>T (p.Asp415Tyr)

gnomAD frequency: 0.00027  dbSNP: rs200836164

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001060994	SCV001225716	uncertain significance	Emery-Dreifuss muscular dystrophy 5, autosomal dominant	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 415 of the SYNE2 protein (p.Asp415Tyr). This variant is present in population databases (rs200836164, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. 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: 855678). 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.
Illumina Laboratory Services, Illumina	RCV001060994	SCV001273144	benign	Emery-Dreifuss muscular dystrophy 5, autosomal dominant	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Revvity Omics, Revvity	RCV001060994	SCV003818848	uncertain significance	Emery-Dreifuss muscular dystrophy 5, autosomal dominant	2019-08-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003393830	SCV004134203	likely benign	not provided	2022-03-01	criteria provided, single submitter	clinical testing	SYNE2: BP4, BS2