Submissions for variant NM_182961.4(SYNE1):c.24488T>C (p.Ile8163Thr)

gnomAD frequency: 0.00045  dbSNP: rs139643725

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000713644	SCV000706202	uncertain significance	not provided	2018-01-24	criteria provided, single submitter	clinical testing
Invitae	RCV000698908	SCV000827598	uncertain significance	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2022-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 8092 of the SYNE1 protein (p.Ile8092Thr). This variant is present in population databases (rs139643725, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 500312). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Athena Diagnostics Inc	RCV000713644	SCV000844271	uncertain significance	not provided	2022-04-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000713644	SCV001770702	uncertain significance	not provided	2020-01-06	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago	RCV001815004	SCV002061987	uncertain significance	not specified	2021-09-23	criteria provided, single submitter	clinical testing	The sequence change, c.24275T>C, in exon 135 results in an amino acid change, p.Ile8092Thr. This sequence change does not appear to have been previously described in individuals with SYNE1-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.096% in the African subpopulation (dbSNP rs139643725). The p.Ile8092Thr change affects a moderately conserved amino acid residue located in a domain of the SYNE1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile8092Thr substitution. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Ile8092Thr change remains unknown at this time.
CeGaT Center for Human Genetics Tuebingen	RCV000713644	SCV002545458	uncertain significance	not provided	2022-05-01	criteria provided, single submitter	clinical testing	SYNE1: PM2
Ambry Genetics	RCV002532521	SCV003568515	uncertain significance	Inborn genetic diseases	2021-07-08	criteria provided, single submitter	clinical testing	The c.24275T>C (p.I8092T) alteration is located in exon 135 (coding exon 134) of the SYNE1 gene. This alteration results from a T to C substitution at nucleotide position 24275, causing the isoleucine (I) at amino acid position 8092 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000713644	SCV003824551	uncertain significance	not provided	2023-12-18	criteria provided, single submitter	clinical testing