ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.3600T>G (p.Asn1200Lys) (rs202049575)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171914 SCV000050914 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000171914 SCV000233539 uncertain significance not provided 2015-10-05 criteria provided, single submitter clinical testing The N1200K variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. The N1200K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the N1200K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Also, this substitution occurs at a position where amino acids with similar properties to Asparagine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000693151 SCV000821007 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-05-07 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 1200 of the DSP protein (p.Asn1200Lys). The asparagine residue is moderately conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs202049575, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 191639). 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.

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