ClinVar Miner

Submissions for variant NM_182961.4(SYNE1):c.23260G>A (p.Val7754Ile) (rs150550013)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000322222 SCV000343088 uncertain significance not provided 2016-12-19 criteria provided, single submitter clinical testing
Invitae RCV000541902 SCV000649131 uncertain significance Spinocerebellar ataxia, autosomal recessive 8; Emery-Dreifuss muscular dystrophy 4, autosomal dominant 2019-11-05 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 7683 of the SYNE1 protein (p.Val7683Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs150550013, ExAC 0.03%). This variant has not been reported in the literature in individuals with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 288855). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000322222 SCV000884642 uncertain significance not provided 2017-09-29 criteria provided, single submitter clinical testing The p.Val7683Ile variant (rs150550013) has not been reported in the medical literature. The p.Val7683Ile variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.02% (identified in 56 out of 276,916 chromosomes), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 288855). The valine at codon 7683 is weakly conserved considering 12 species (Alamut software v2.10.0), and computational analyses predict that this variant does not affect the structure/function of the SYNE1 protein (SIFT: tolerated, PolyPhen2: benign, MutationTaster: polymorphism). However, based on the available information, the clinical significance of the p.Val7683Ile variant cannot be determined with certainty.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000322222 SCV001154914 uncertain significance not provided 2018-09-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001157122 SCV001318668 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001157123 SCV001318669 uncertain significance Spinocerebellar ataxia, autosomal recessive 8 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.

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