Submissions for variant NM_182914.3(SYNE2):c.13826A>C (p.Asn4609Thr)

gnomAD frequency: 0.00001  dbSNP: rs751525888

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001330574	SCV001522295	uncertain significance	Emery-Dreifuss muscular dystrophy 5, autosomal dominant	2019-08-08	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV001330574	SCV002148897	uncertain significance	Emery-Dreifuss muscular dystrophy 5, autosomal dominant	2021-01-20	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change replaces asparagine with threonine at codon 4609 of the SYNE2 protein (p.Asn4609Thr). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and threonine. This variant is present in population databases (rs751525888, ExAC 0.006%). This variant has not been reported in the literature in individuals with SYNE2-related conditions. 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV001330574	SCV004176507	uncertain significance	Emery-Dreifuss muscular dystrophy 5, autosomal dominant	2023-02-14	criteria provided, single submitter	clinical testing	The missense c.13826A>C (p.Asn4609Thr) variant in SYNE2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Asn4609Thr variant is reported with an allele frequency of 0.002% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain Significance (multiple submissions). The amino acid change p.Asn4609Thr in SYNE2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The p.Asn4609Thr variant is novel (not in any individuals) in 1000 Genomes. The amino acid Asn at position 4609 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001330574	SCV004806430	uncertain significance	Emery-Dreifuss muscular dystrophy 5, autosomal dominant	2024-03-25	criteria provided, single submitter	clinical testing