Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000808837 | SCV000948961 | pathogenic | DK1-congenital disorder of glycosylation | 2025-01-27 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 520 of the DOLK protein (p.Thr520Ala). This variant is present in population databases (rs374860681, gnomAD 0.005%). This missense change has been observed in individual(s) with DOLK-congenital disorder of glycosylation (PMID: 28816422, 34956305). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 653127). 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 DOLK protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002397659 | SCV002704925 | uncertain significance | Cardiovascular phenotype | 2023-06-21 | criteria provided, single submitter | clinical testing | The p.T520A variant (also known as c.1558A>G), located in coding exon 1 of the DOLK gene, results from an A to G substitution at nucleotide position 1558. The threonine at codon 520 is replaced by alanine, an amino acid with similar properties. This variant has been detected in trans with a DOLK nonsense alteration in two siblings with severe neonatal presentations with findings that included severe icthyosis, distal digital truncations, and dilated cardiomyopathy with and without non-compaction cardiomyopathy (Rush ET et al. Am. J. Med. Genet. A, 2017 Sep;173:2428-2434). This variant has been detected in trans with a DOLK missense variant in two related cases with lethal ichthyosis, distal digital constrictions, cardiomegaly and additional findings (Komlosi K et al. Front Genet. 2021 Dec;12:719624). This variant was also detected in an exome sequencing referral cohort; however, details were not provided (Retterer K et al. Genet. Med., 2016 07;18:696-704). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV000808837 | SCV002791925 | likely pathogenic | DK1-congenital disorder of glycosylation | 2024-04-12 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV003413622 | SCV004116284 | likely pathogenic | DOLK-related disorder | 2023-10-05 | criteria provided, single submitter | clinical testing | The DOLK c.1558A>G variant is predicted to result in the amino acid substitution p.Thr520Ala. This variant has been reported in the compound heterozygous state in two families with DOLK-related disease (Rush et al. 2017. PubMed ID: 28816422; Komlosi et al. 2021. PubMed ID: 34956305). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-131708025-T-C). This variant is interpreted as likely pathogenic. |
| Mayo Clinic Laboratories, |
RCV004792499 | SCV005413921 | likely pathogenic | not provided | 2023-12-05 | criteria provided, single submitter | clinical testing | PP1_strong, PP4, PM3 |