Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000756054 | SCV000883765 | uncertain significance | not provided | 2017-12-28 | criteria provided, single submitter | clinical testing | The DYNC2H1 c.2996C>T; p.Thr999Ile variant (rs753542063), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.005% (identified on 14 out of 244,104 chromosomes). The threonine at position 999 is highly conserved, considering 28 species (Alamut software v.2.20.0) and computational analyses of the effects of the p.Thr999Ile variant on protein structure and function do not agree (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign, Align GVGD: Class C15). Based on the available information, the clinical significance of the p.Thr999Ile variant cannot be determined with certainty. |
| Invitae | RCV001855869 | SCV002315867 | uncertain significance | Jeune thoracic dystrophy | 2022-01-16 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 999 of the DYNC2H1 protein (p.Thr999Ile). This variant is present in population databases (rs753542063, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with DYNC2H1-related conditions. ClinVar contains an entry for this variant (Variation ID: 618073). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DYNC2H1 protein function. 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. |