ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs749730642
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001537824 SCV000233617 likely benign not provided 2019-07-24 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 31402444, 21723241, 26138720, 24070718, 20152563, 20129281, 20524011)
Laboratory for Molecular Medicine, Mass General Brigham 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 likely benign Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 2023-12-11 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000771384 SCV000903708 uncertain significance Cardiomyopathy 2021-02-19 criteria provided, single submitter clinical testing This missense variant replaces leucine with proline at codon 1654 of the DSP protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported 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 also been reported in an individual affected with left ventricular non-compaction cardiomyopathy (PMID: 31568572). This variant has been identified in 8/250726 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Klaassen Lab, Charite University Medicine Berlin RCV000853137 SCV000995850 uncertain significance Left ventricular noncompaction cardiomyopathy 2019-07-03 criteria provided, single submitter research
Ambry Genetics RCV002345629 SCV002645756 uncertain significance Cardiovascular phenotype 2019-12-21 criteria provided, single submitter clinical testing The p.L1654P variant (also known as c.4961T>C), located in coding exon 23 of the DSP gene, results from a T to C substitution at nucleotide position 4961. The leucine at codon 1654 is replaced by proline, an amino acid with similar properties. This variant co-occurred with additional alterations in the PKP2 gene in a family reported to have arrhythmogenic right ventricular cardiomyopathy (ARVC); however, p.L1654P was not seen in isolation, complicating interpretation of the segregation data (Bauce B et al. Heart Rhythm, 2010 Jan;7:22-9; Xu T et al. J. Am. Coll. Cardiol., 2010 Feb;55:587-97; Rigato I et al. Circ Cardiovasc Genet, 2013 Dec;6:533-42). This variant has also been detected in an individual from a pediatric cardiomyopathy cohort who was reported to have left ventricular non-compaction cardiomyopathy; however, details were limited (K&uuml;hnisch J et al. Clin. Genet., 2019 Dec;96:549-559), and in an exome sequencing cohort in an individual not know to have cardiomyopathy (Haggerty CM et al. Genet. Med., 2017 11;19:1245-1252). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV003996651 SCV004836373 uncertain significance Arrhythmogenic cardiomyopathy with wooly hair and keratoderma 2024-01-11 criteria provided, single submitter clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001537824 SCV001955708 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001537824 SCV001965239 uncertain significance not provided no assertion criteria provided clinical testing

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