ClinVar Miner

Submissions for variant NM_182961.4(SYNE1):c.4822G>A (p.Ala1608Thr)

gnomAD frequency: 0.00106  dbSNP: rs138617999
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000713672 SCV000229885 uncertain significance not provided 2018-01-11 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000324886 SCV000461481 benign Emery-Dreifuss muscular dystrophy 4, autosomal dominant 2018-01-13 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 Laboratory Services, Illumina RCV000379472 SCV000461482 uncertain significance Autosomal recessive ataxia, Beauce type 2018-01-13 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.
Invitae RCV000560151 SCV000649184 uncertain significance Autosomal recessive ataxia, Beauce type; Emery-Dreifuss muscular dystrophy 4, autosomal dominant 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1615 of the SYNE1 protein (p.Ala1615Thr). This variant is present in population databases (rs138617999, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of spinocerebellar ataxia (PMID: 31692161). ClinVar contains an entry for this variant (Variation ID: 197018). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 RCV000713672 SCV000714054 likely benign not provided 2020-04-17 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 31692161)
Athena Diagnostics Inc RCV000713672 SCV000844299 likely benign not provided 2020-04-17 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000713672 SCV001157718 uncertain significance not provided 2019-08-13 criteria provided, single submitter clinical testing The SYNE1 c.4843G>A; p.Ala1615Thr variant (rs138617999), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 197018). This variant is found in the non-Finnish European population with an overall allele frequency of 0.15% (195/126496 alleles) in the Genome Aggregation Database. The alanine at codon 1615 is weakly conserved and is found as a threonine in multiple mammalian species, and computational analyses (SIFT: tolerated, PolyPhen-2: benign) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Ala1615Thr variant is uncertain at this time.
Institute of Human Genetics, University of Leipzig Medical Center RCV000379472 SCV001441085 benign Autosomal recessive ataxia, Beauce type 2019-01-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000713672 SCV002542253 uncertain significance not provided 2021-04-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003317128 SCV004021257 uncertain significance not specified 2023-06-05 criteria provided, single submitter clinical testing Variant summary: SYNE1 c.4843G>A (p.Ala1615Thr) results in a non-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 0.00079 in 251218 control chromosomes in the gnomAD database, including 1 homozygote. c.4843G>A has been reported in the literature in at least one individual affected with ataxia without strong evidence for causality (e.g., Ngo_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31692161). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Four laboratories classified the variant as a variant of uncertain significance, three laboratories classified it as likely benign, one laboratory classified it as benign, and one laboratory classified it with conflicting interpretations (VUS/B). Based on the evidence outlined above, the variant was classified as uncertain significance.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001252118 SCV001427867 likely benign Intellectual disability 2019-01-01 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000713672 SCV002034946 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000713672 SCV002037774 likely benign not provided no assertion criteria provided clinical testing

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