ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.5161_5163GAA[2] (p.Glu1723del) (rs730880091)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618937 SCV000736259 uncertain significance Cardiovascular phenotype 2016-08-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Blueprint Genetics RCV000157215 SCV000206939 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-11-05 no assertion criteria provided clinical testing
GeneDx RCV000766883 SCV000233695 uncertain significance not provided 2018-03-28 criteria provided, single submitter clinical testing The c.5167_5169delGAA variant results in an in-frame deletion of a glutamic acid (E) residue at position 1723. This variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, c.5167_5169delGAA has been classified in ClinVar as a variant of uncertain significance by an external laboratory (SCV000271732.1; Landrum et al., 2016). In addition, c.5167_5169delGAA has been observed in one other individual referred to GeneDx for cardiomyopathy testing and segregated with a DCM phenotype in three affected family members. Furthermore, this 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. Other in-frame deletions in the DSP gene have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014), and at least two in silico models predict this amino acid deletion is probably damaging to the protein structure/function. Nonetheless, this variant lacks functional evidence and observation in a significant number of affected individuals, which would further clarify pathogenicityTherefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000477320 SCV000543272 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-11-12 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 23 of the DSP mRNA (c.5167_5169delGAA). This leads to the deletion of 1 amino acid residue in the DSP protein (p.Glu1723del) but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs730880091, ExAC 0.009%) but has not been reported in the literature in individuals with a DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 199944). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. In summary, this variant is a rare in-frame deletion with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000222434 SCV000271732 uncertain significance not specified 2015-04-14 criteria provided, single submitter clinical testing The p.Glu1721[2] variant in DSP has not been previously reported in individuals with cardiomyopathy, but has been identified in 2/66410 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). This va riant deletes one of 3 glutamic acid residues (first unit at positions 1721-1723 ). It is unclear if this change will have an impact on protein function. In summ ary, the clinical significance of the p.Glu1721[2] variant is uncertain.

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