ClinVar Miner

Submissions for variant NM_014908.3(DOLK):c.560G>T (p.Arg187Leu) (rs377658203)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000639753 SCV000761334 uncertain significance Congenital disorder of glycosylation type 1M 2017-08-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 187 of the DOLK protein (p.Arg187Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs377658203, ExAC 0.003%). This variant has not been reported in the literature in individuals with DOLK-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786301 SCV000925064 uncertain significance not provided 2017-10-25 no assertion criteria provided provider interpretation Found in a Caucasian teenager with a new diagnosis of HCM and a long history of prolonged QTc intervals. He had a 130-gene Arrhythmia and Cardiomyopathy Comprehensive Panel with the Invitae laboratory. Results showed 4 variants: -p.Arg187Leu (c.560G>T) in the DOLK gene -p.Leu691Phe (c.2071C>T) in the DSP gene -p.Gly1546Ser (c.4636G>A) in the FLNC gene -p.Arg216Gln (c.647G>A) in the JUP gene p.Arg187Leu (c.560G>T) in exon 1 of the DOLK gene (NM_014908.3) Chromosome location 9:131709023 C / A Based on the information reviewed below, we classify this as a Variant of Uncertain Significance, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has not previously been reported in the literature in association with disease, according to the Invitae report. The DOLK gene is associated with the autosomal recessive congenital disorder of glycosylation DOLK-CDG (CDG-Im) (MedGen UID 332072). The clinical significance of this variant is uncertain at this time, although because DOLK-CDG is autosomal recessive, any single variant is likely insufficient as an explanation for disease. This is a nonconservative acid change, resulting in the replacement of a positively-charged Arginine with a nonpolar Leucine. Arginine at this location is very highly conserved across ~100 vertebrate species for which we have data (it is a Cysteine in one species of bat). The adjacent residues are also highly conserved. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Of the SNP variants listed in ClinVar as Pathogenic, all are missense. This variant was reported in 4 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 3 non-Finnish European individuals (MAF 0.003%) and 1 individual with “Other” ancestry. Overall MAF 0.002%. There is good sequencing coverage at this site. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.

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