Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001950256 | SCV002211803 | likely pathogenic | Jeune thoracic dystrophy | 2025-01-20 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1987 of the DYNC2H1 protein (p.Thr1987Met). This variant is present in population databases (rs769618486, gnomAD 0.03%). 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: 1439810). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DYNC2H1 protein function with a positive predictive value of 95%. This variant disrupts the p.Thr1987 amino acid residue in DYNC2H1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19442771). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| Ambry Genetics | RCV002562201 | SCV003755624 | uncertain significance | Inborn genetic diseases | 2021-12-03 | criteria provided, single submitter | clinical testing | The c.5960C>T (p.T1987M) alteration is located in exon 38 (coding exon 38) of the DYNC2H1 gene. This alteration results from a C to T substitution at nucleotide position 5960, causing the threonine (T) at amino acid position 1987 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Gene |
RCV003154224 | SCV003842514 | uncertain significance | not provided | 2023-03-16 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004699573 | SCV005202158 | uncertain significance | not specified | 2024-07-01 | criteria provided, single submitter | clinical testing | Variant summary: DYNC2H1 c.5960C>T (p.Thr1987Met) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 248208 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia (4.4e-05 vs 0.0025), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.5960C>T in individuals affected with Short-rib thoracic dysplasia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1439810). Based on the evidence outlined above, the variant was classified as uncertain significance. |