ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.2540T>C (p.Leu847Pro) (rs1064794215)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588189 SCV000568235 uncertain significance not provided 2018-07-25 criteria provided, single submitter clinical testing The L847P variant in the PKP2 gene has been reported in at least two individuals in association with ARVC (Watkins et al., 2009; Walsh et al., 2017), although no segregation studies were described. This variant is not observed in large population cohorts (Lek et al., 2016). The L847P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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.
Integrated Genetics/Laboratory Corporation of America RCV000588189 SCV000698475 uncertain significance not provided 2017-03-27 criteria provided, single submitter clinical testing Variant summary: The PKP2 c.2540T>C (p.Leu847Pro) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121406 control chromosomes and was reported in an affected individual in the literature, without strong evidence for causality (Watkins_2009). Taken together, until additional clinical and functional data becomes available, this variant is classified as VUS.

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