ClinVar Miner

Submissions for variant NM_001376.5(DYNC1H1):c.13349C>T (p.Thr4450Met) (rs146087540)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000421113 SCV000535287 uncertain significance not provided 2018-02-02 criteria provided, single submitter clinical testing The T4450M variant in the DYNC1H1 gene has been reported as a variant of unknown clinical significance in a patient with a complex phenotype; however, it was not identified in a clinically affected sibling (Antoniadi et al., 2015). The T4450M variant is observed in 30/277174 (0.01%) alleles in large population cohorts (Lek et al., 2016. The T4450M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret T4450M as a variant of uncertain significance.
Invitae RCV000544383 SCV000651617 uncertain significance Charcot-Marie-Tooth disease, axonal, type 2O 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 4450 of the DYNC1H1 protein (p.Thr4450Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs146087540, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with Inherited peripheral neuropathy, however the patient's affected sibling did not carry this variant (PMID: 26392352). ClinVar contains an entry for this variant (Variation ID: 392076). 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.

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