ClinVar Miner

Submissions for variant NM_001376.5(DYNC1H1):c.4532C>T (p.Pro1511Leu) (rs1327664377)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000549631 SCV000651646 uncertain significance Charcot-Marie-Tooth disease, axonal, type 2O 2017-03-31 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1511 of the DYNC1H1 protein (p.Pro1511Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Pediatric Genomics Discovery Program,Yale University RCV001004062 SCV001156515 likely pathogenic Progressive muscle weakness 2020-02-06 criteria provided, single submitter research The p.Pro1511Leu variant in DYNC1H1 has not been reported prior to this entry, and is absent from controls (PM2). It was identified to be de novo (PS2) in a patient with progressive muscular weakness and atrophy affecting the upper and lower extremities, extraocular muscles, and vocal cords. She has progressive contractures and restrictive pulmonary disease from severe scoliosis. Her most recent EMG shows severe chronic pure motor neuropathy/neuronopathy. This residue is highly conserved in species. Multiple lines of in silico predictors suggest damaging effect of this amino acid substitution (PP3). DYNC1H1 is a gene with a low rate of benign missense change, whereas most pathogenic variants in this gene are missense (PP2). The p.Pro1511Leu variant is located in the stem domain which is where dimerization occurs; other variants in this domain have been associated with lower-extremity predominant spinal muscular atrophy (PM1).

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