ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.4961T>C (p.Leu1654Pro) (rs749730642)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000219274 SCV000233617 likely benign not specified 2016-06-23 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000219274 SCV000271731 uncertain significance not specified 2015-04-04 criteria provided, single submitter clinical testing The p.Leu1654Pro variant has been previously reported in at least 2 adults with ARVC (Bauce 2010, Xu 2010, Bauce 2011, Rigato 2013 - note that some of these stu dies had overlapping cohorts). In one family (Bauce 2010), the proband carried 2 additional PKP2 variants (one of them being a nonsense variant). Family studies were inconclusive but it is worth noting that the DSP Leu1654Pro variant was in herited from the affected father while the PKP2 nonsense variant was inherited f rom the unaffected mother. This variant has also been identified in 1 homozygous individual (2/119956 alleles) by the Exome Aggregation Consortium (http://exac. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Leu1654Pro variant is uncertain.
Invitae RCV000457559 SCV000543218 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-05-29 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1654 of the DSP protein (p.Leu1654Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs749730642, ExAC <0.01%). This variant has been reported in the literature in a family affected with arrhythmogenic right ventricular cardiomyopathy, however, in one individual the variant did not segregate with disease and in several affected individuals it presented with a pathogenic variant in a different gene (PMID: 24070718, 20129281) and in unrelated individuals with this condition (PMID: 28471438). ClinVar contains an entry for this variant (Variation ID: 199885). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000771384 SCV000903708 uncertain significance Cardiomyopathy 2018-10-29 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the central rod domain of the DSP protein that is thought to form a dimeric coiled coil. 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 RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy but it did not segregate with disease in the family (PMID: 20129281). This variant has been identified in 7/245692 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Klaassen Lab,Charite University Medicine Berlin RCV000853137 SCV000995850 uncertain significance Left ventricular noncompaction cardiomyopathy 2019-07-03 criteria provided, single submitter research

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