ClinVar Miner

Submissions for variant NM_182961.4(SYNE1):c.19544T>C (p.Phe6515Ser) (rs747674900)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000693138 SCV000820994 uncertain significance Spinocerebellar ataxia, autosomal recessive 8; Emery-Dreifuss muscular dystrophy 4, autosomal dominant 2018-03-02 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 6444 of the SYNE1 protein (p.Phe6444Ser). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is present in population databases (rs747674900, ExAC 0.02%). This variant has not been reported in the literature in individuals with SYNE1-related disease. 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 tolerated, 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756741 SCV000884640 uncertain significance not provided 2017-09-05 criteria provided, single submitter clinical testing The p.Phe6444Ser variant (rs747674900) has not been reported in the medical literature, and it is not listed in gene-specific variant databases. This variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.016% in the non-Finnish European population (identified in 20 out of 126,680 chromosomes; 0 homozygotes). The phenylalanine at codon 6444 is weakly conserved considering 12 species (Alamut software v2.9.0), and computational analyses suggest that this variant does not affect the SYNE1 protein structure/function (SIFT: tolerated, PolyPhen2: benign, MutationTaster: polymorphism). However, based on the available information, the clinical significance of the p.Phe6444Ser variant cannot be determined with certainty.

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