Submissions for variant NM_001376.5(DYNC1H1):c.1466C>T (p.Thr489Met) (rs773725715)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000527924	SCV000651624	uncertain significance	Charcot-Marie-Tooth disease, axonal, type 2O	2019-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 489 of the DYNC1H1 protein (p.Thr489Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs773725715, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with DYNC1H1-related disease. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics	RCV000717290	SCV000848139	likely benign	History of neurodevelopmental disorder	2018-01-30	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);Does not segregate with disease in family study (genes with incomplete penetrance)

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