ClinVar Miner

Submissions for variant NM_014908.3(DOLK):c.898C>T (p.Leu300Phe) (rs371529625)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000432774 SCV000535208 uncertain significance not provided 2017-07-10 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DOLK gene. The L300F variant has not been published as pathogenic or been reported as benign to our knowledge. It is observed in 3/11576 (0.026%) alleles from individuals of Latino background in the ExAC dataset, though no individuals were reported to be homozygous (Lek et al., 2016). The L300F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000557113 SCV000638527 uncertain significance Congenital disorder of glycosylation type 1M 2018-07-13 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 300 of the DOLK protein (p.Leu300Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs371529625, ExAC 0.03%) but has not been reported in the literature in individuals with a DOLK-related disease. ClinVar contains an entry for this variant (Variation ID: 392015). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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