ClinVar Miner

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

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Total submissions: 7
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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.

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