Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000549631 | SCV000651646 | likely pathogenic | Charcot-Marie-Tooth disease axonal type 2O | 2022-06-27 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 472535). This missense change has been observed in individual(s) with DYNC1H1-related disorders (PMID: 32656949). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1511 of the DYNC1H1 protein (p.Pro1511Leu). |
| Pediatric Genomics Discovery Program, |
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). |