ClinVar Miner

Submissions for variant NM_014908.4(DOLK):c.1262T>C (p.Leu421Pro)

gnomAD frequency: 0.00003  dbSNP: rs145125254
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000798237 SCV000937840 uncertain significance DK1-congenital disorder of glycosylation 2022-08-16 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 421 of the DOLK protein (p.Leu421Pro). This variant is present in population databases (rs145125254, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of DOLK-related conditions (PMID: 32250540). ClinVar contains an entry for this variant (Variation ID: 644343). 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"). 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.
Ambry Genetics RCV002442643 SCV002677482 uncertain significance Cardiovascular phenotype 2022-04-28 criteria provided, single submitter clinical testing The p.L421P variant (also known as c.1262T>C), located in coding exon 1 of the DOLK gene, results from a T to C substitution at nucleotide position 1262. The leucine at codon 421 is replaced by proline, an amino acid with similar properties. This variant was detected in trans with a second DOLK missense variant in a family with fatal hyperkeratosis syndrome (Hall BD et al. Am J Med Genet A, 2020 06;182:1421-1425). 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, Fulgent Genetics RCV000798237 SCV002777988 uncertain significance DK1-congenital disorder of glycosylation 2021-10-08 criteria provided, single submitter clinical testing
GeneDx RCV004822206 SCV005442921 uncertain significance not provided 2024-07-05 criteria provided, single submitter clinical testing Identified with a second DOLK variant in trans in a family with four infants who died of fatal hyperkeratosis syndrome with heart block and cardiorespiratory arrest (PMID: 32250540); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34956305, 32250540)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV005056563 SCV005726037 uncertain significance not specified 2024-11-22 criteria provided, single submitter clinical testing Variant summary: DOLK c.1262T>C (p.Leu421Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251278 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in DOLK causing DK1-congenital disorder of glycosylation (4e-05 vs 0.0011), allowing no conclusion about variant significance. c.1262T>C has been reported in the literature in at least an individual affected with clinical features of dolichol kinase deficiency (example: Hall_AJMGA_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32250540). ClinVar contains an entry for this variant (Variation ID: 644343). Based on the evidence outlined above, the variant was classified as uncertain significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.