Submissions for variant NM_182961.4(SYNE1):c.15202A>G (p.Lys5068Glu)

gnomAD frequency: 0.00021  dbSNP: rs139805184

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726244	SCV000343130	uncertain significance	not provided	2018-04-24	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000726244	SCV000615565	uncertain significance	not provided	2024-06-11	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Polyphen and MutationTaster predict this amino acid change may be benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850434	SCV002256811	uncertain significance	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 4997 of the SYNE1 protein (p.Lys4997Glu). This variant is present in population databases (rs139805184, gnomAD 0.02%). 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: 288888). 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 tolerated. 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.
GeneDx	RCV000726244	SCV002540554	uncertain significance	not provided	2025-04-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002518060	SCV003530910	uncertain significance	Inborn genetic diseases	2021-09-30	criteria provided, single submitter	clinical testing	The c.14989A>G (p.K4997E) alteration is located in exon 78 (coding exon 77) of the SYNE1 gene. This alteration results from a A to G substitution at nucleotide position 14989, causing the lysine (K) at amino acid position 4997 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000726244	SCV003824035	uncertain significance	not provided	2019-10-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000290140	SCV004122494	uncertain significance	not specified	2023-09-28	criteria provided, single submitter	clinical testing	Variant summary: SYNE1 c.14989A>G (p.Lys4997Glu), also known as c.15202A>G (p.Lys5068Glu), results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 282834 control chromosomes (gnomAD). To our knowledge, no occurrence of c.14989A>G in individuals affected with Emery-Dreifuss Muscular Dystrophy 4, Autosomal Dominant and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters have assessed the variant since 2014, and all six classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.