ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.1323G>C (p.Lys441Asn) (rs1037212969)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498264 SCV000590294 uncertain significance not provided 2017-06-07 criteria provided, single submitter clinical testing The K441N variant of uncertain significance in the DSP gene has been reported in one individual who also harbored the c.2146-1 G>C pathogenic variant in the PKP2 gene (Abrams et al., 2015), though no segregation data is available to determine of the K441N variant in the DSP gene independently segregated with disease. This variant was not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server), indicating it is not a common benign variant. The K441N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Moreover, this substitution occurs at a position that is highly conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Thus, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000641782 SCV000763431 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-08-24 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 441 of the DSP protein (p.Lys441Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DSP-related disease. 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, 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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