ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.8536C>G (p.Arg2846Gly) (rs397516972)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038113 SCV000061779 uncertain significance not specified 2012-06-30 criteria provided, single submitter clinical testing The Arg2846Gly variant in DSP has not been reported in the literature, but has b een listed in the ARVC Mutation Database (http://arvcdatabase.info/) without any additional information. Computational analyses (biochemical amino acid properti es, conservation, AlignGVGD, and PolyPhen2) suggest that it may impact the prote in, though this information is not predictive enough to determine pathogenicity. The variant has not been detected in 2 very large and broad populations (Europe an and African American) screened by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/). This low frequency is consistent with a pathogenic role but is insufficient to establish this with confidence. Additional informat ion is needed to fully assess the clinical significance of the Arg2846Gly varian t.
GeneDx RCV000658263 SCV000780034 uncertain significance not provided 2018-05-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The R2846G variant has been reported in one individual in association with ARVC, although no further clinical details or segregation studies were described (Adler et al., 2016). This variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R2846G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, this variant has not been observed in a significant number of affected individuals, and it lacks both segregation and functional studies which would further clarify its pathogenicity. Finally, R2846G is also classified as a variant of uncertain significance in ClinVar by another clinical laboratory (SCV000061779.5; Landrum et al., 2016).

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