Submissions for variant NM_182961.4(SYNE1):c.13849A>C (p.Asn4617His) (rs147667464)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000713598	SCV000338296	uncertain significance	not provided	2018-09-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000713598	SCV000589362	uncertain significance	not provided	2017-11-21	criteria provided, single submitter	clinical testing	The N4546H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N4546H variant is observed in 11/66736 (0.016%) alleles and in 3/16510 (0.018%) from individuals of European and South Asian background, respectively (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This 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 that is conserved across species; however, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with FLNC-related disorders (Stenson et al., 2014). 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	RCV000713598	SCV000844223	uncertain significance	not provided	2018-08-22	criteria provided, single submitter	clinical testing
Invitae	RCV000811161	SCV000951414	uncertain significance	Spinocerebellar ataxia, autosomal recessive 8; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2019-05-13	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with histidine at codon 4546 of the SYNE1 protein (p.Asn4546His). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is present in population databases (rs147667464, ExAC 0.02%). This variant has not been reported in the literature in individuals with SYNE1-related disease. ClinVar contains an entry for this variant (Variation ID: 285328). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000713598	SCV001154935	uncertain significance	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001158275	SCV001319895	uncertain significance	Spinocerebellar ataxia, autosomal recessive 8	2018-01-15	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 Clinical Services Laboratory,Illumina	RCV001158276	SCV001319896	uncertain significance	Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2018-01-15	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.