Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001389363 | SCV001590689 | pathogenic | Charcot-Marie-Tooth disease axonal type 2O | 2022-02-10 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with spinal muscular atrophy (Invitae). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt DYNC1H1 protein function. ClinVar contains an entry for this variant (Variation ID: 1075692). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 580 of the DYNC1H1 protein (p.Glu580Ala). |
| New York Genome Center | RCV004554862 | SCV005044174 | likely pathogenic | Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures; Charcot-Marie-Tooth disease axonal type 2O; Intellectual disability, autosomal dominant 13 | 2022-12-23 | criteria provided, single submitter | clinical testing | The de novo heterozygous c.1739A>C p.(Glu580Ala) missense variant identified in the DYNC1H1 gene has not been reported in affected individuals in the literature. This variant has a single entry in the ClinVar database as Pathogenic [Variation ID: 1075692]. The variant is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.1739A>C variant is located in exon 8 of this 78-exon gene and is predicted to replace a highly conserved glutamic acid residue with alanine at position 580 within the STEM domain [dimerization sub-domain] of the encoded protein [PMID: 32656949]. In silico predictions are in favor of the variant’s damaging effect [REVEL = 0.651]; however, functional studies to support or refute these predictions have not been reported. A different missense variant affecting the same Glu580 residue [c.1738G>A p.(Glu580Lys)] has been reported in two fetuses with micro-lissencephaly and arthrogryposis [PMID:26395554] and has been deposited in ClinVar database as Pathogenic/Likely Pathogenic [Variation ID: 208862]. Based on the available evidence, the heterozygous c.1739A>C p.(Glu580Ala) missense variant identified in the DYNC1H1 gene is reported as Likely Pathogenic. |