ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.2552T>A (p.Leu851Gln) (rs111368396)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769220 SCV000900596 uncertain significance Cardiomyopathy 2017-02-28 criteria provided, single submitter clinical testing
Color RCV000769220 SCV000904671 uncertain significance Cardiomyopathy 2018-06-26 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in spectrin repeat 8 of the plakin domain of the DSP protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual with unexplained sudden cardiac death (PMID: 27332903). This variant has been identified in 18/277198 chromosomes (17/126700 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000181301 SCV000233592 uncertain significance not provided 2018-11-28 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The L851Q variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 17/126700 (0.013%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). Nevertheless, the L851Q variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000524989 SCV000641296 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-08-08 criteria provided, single submitter clinical testing This sequence change replaces leucine with glutamine at codon 851 of the DSP protein (p.Leu851Gln). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and glutamine. This variant is present in population databases (rs111368396, ExAC 0.006%). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 199870). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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