Submissions for variant NM_182961.4(SYNE1):c.24338T>G (p.Phe8113Cys) (rs769930534)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000262381	SCV000340880	uncertain significance	not provided	2016-03-29	criteria provided, single submitter	clinical testing
Invitae	RCV000544060	SCV000649137	uncertain significance	Spinocerebellar ataxia, autosomal recessive 8; Emery-Dreifuss muscular dystrophy 4, autosomal dominant	2017-06-05	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine with cysteine at codon 8042 of the SYNE1 protein (p.Phe8042Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is present in population databases (rs769930534, ExAC 0.03%). This variant has not been reported in the literature in individuals with a SYNE1-related disease. ClinVar contains an entry for this variant (Variation ID: 287184). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant has uncertain impact on SYNE1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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