Submissions for variant NM_182961.4(SYNE1):c.13768A>G (p.Asn4590Asp)

gnomAD frequency: 0.00019  dbSNP: rs199761238

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725051	SCV000333546	uncertain significance	not provided	2016-08-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000725051	SCV000589361	uncertain significance	not provided	2017-08-21	criteria provided, single submitter	clinical testing	The N4519D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N4519D variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Asparagine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Athena Diagnostics Inc	RCV000725051	SCV000615558	uncertain significance	not provided	2023-05-08	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 higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging.
Invitae	RCV000647673	SCV000769471	uncertain significance	Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 4519 of the SYNE1 protein (p.Asn4519Asp). This variant is present in population databases (rs199761238, gnomAD 0.03%). 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: 282206). 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	RCV001152801	SCV001314035	uncertain significance	Autosomal recessive ataxia, Beauce type	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001152802	SCV001314036	likely benign	Emery-Dreifuss muscular dystrophy 4, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Ambry Genetics	RCV002518844	SCV003639519	uncertain significance	Inborn genetic diseases	2022-06-09	criteria provided, single submitter	clinical testing	The c.13555A>G (p.N4519D) alteration is located in exon 77 (coding exon 76) of the SYNE1 gene. This alteration results from an A to G substitution at nucleotide position 13555, causing the asparagine (N) at amino acid position 4519 to be replaced by an aspartic acid (D). Based on data from gnomAD, the G allele has an overall frequency of 0.02% (48/282738) total alleles studied. The highest observed frequency was 0.03% (41/129128) of European (non-Finnish) alleles. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000725051	SCV003826354	uncertain significance	not provided	2022-08-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725051	SCV004702758	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing	SYNE1: PM2:Supporting
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000725051	SCV001809457	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000725051	SCV001968967	uncertain significance	not provided		no assertion criteria provided	clinical testing