Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000427964 | SCV000533490 | likely pathogenic | not provided | 2016-11-09 | criteria provided, single submitter | clinical testing | The I609M variant in the DYNC1H1 gene has not been reported previously as a pathogenic variant,nor as a benign variant, to our knowledge. The I609M variant was not observed in approximately6500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. The I609M variant is aconservative amino acid substitution, which is not likely to impact secondary protein structure asthese residues share similar properties. However, this substitution occurs within the dimerizationdomain at a position that is conserved across species and in silico analysis predicts this variant isprobably damaging to the protein structure/function. While not published in a peer reviewed journal, adifferent missense variant in the same codon (I609T) was identified by whole exome sequencing in alarge kindred with bilateral proximal lower limb muscle weakness and atrophy (Si Y., 2016), supportingthe functional importance of this residue in the protein. The I609M variant is a strong candidate for apathogenic variant |
| Invitae | RCV000806150 | SCV000946132 | uncertain significance | Charcot-Marie-Tooth disease axonal type 2O | 2018-10-23 | criteria provided, single submitter | clinical testing | 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. 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"). This variant has not been reported in the literature in individuals with DYNC1H1-related disease. ClinVar contains an entry for this variant (Variation ID: 390612). This variant is present in population databases (rs760971556, ExAC 0.006%). This sequence change replaces isoleucine with methionine at codon 609 of the DYNC1H1 protein (p.Ile609Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. |