ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.2245_2246delinsAT (p.Ala749Ile) (rs1565574704)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786189 SCV000924897 uncertain significance not provided 2017-04-21 no assertion criteria provided provider interpretation This patient has a diagnosis of HCM and had a Comprehensive Cardiomyopathy Panel with the GeneDx laboratory. The test included sequencing of 76 genes and additional deletion/duplication analysis of 60 of those genes (nuclear genes) associated with various forms of cardiomyopathy: ABCC9, ACTC (ACTC1), ACTN2, ANKRD1, BAG3 , BRAF, CAV3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL , NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. 7 variants were reported. We believe the MYH7 variant is the most likely to be pathogenic: • p.Ala868Pro (A868P; c.2602G>C) in the MYH7 gene • p.Leu327Val (L327V; c.979C>G) in the PRKAG2 gene • p.Pro323Thr (P323T; c.967C>A) in the GLA gene • p.Ala749Ile (A749I; c.2245_2246delGCinsAT) in the PKP2 gene • p.Met89Thr (M89T; c.266T>C) in the JUP gene • p.Asp2771Ala (D2771A; c.8312A>C) in the DMD gene • Duplication of at least exons 1-2 of the LAMA4 gene Given the large number of genes included on this panel, and the large and variable nature of some of these genes, it is expected that most individuals (including individuals who don't have inherited cardiac disease) would have at least one and possibly several rare variants found with this test. As a result, it is important to consider the data available on each variant to determine whether it is a disease-predisposing variant or one of the many benign rare variants that we all have in our DNA. p.Ala749Ile (A749I; c.2245_2246delGCinsAT) in exon 11 of the PKP2 gene (NM_004572.3) Chromosome position: 12:32955390 GC / AT Based on the information reviewed below, we classify this as a Variant of Uncertain Significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. Of note, the PKP2 gene is associated with ARVC, which is not our patient’s phenotype. Furthermore, this variant did not segregate with HCM in this patient’s affected daughter. Of note, Kapplinger et al. (2011) from Dr. Michael Ackerman’s group at Mayo Clinic have reported a significant yield of rare missense variants in the ARVC genes of presumably healthy controls from various ethnicities, including PKP2. According to their data, 16% of 427 controls hosted missense variants—similar to the 21% yield in 175 Dutch and U.S. ARVC cases. This is a reminder that missense variants of unknown significance in ARVC-related genes need to be interpreted with particular caution. Splice-site-disrupting, frameshift, or other “radical” variants are more likely than missense variants to be disease-causing in PKP2 (Kapplinger et al. 2011). This variant has not been reported in the literature in association with disease. This is a conservative amino acid change, resulting in the replacement of a nonpolar Alanine with a nonpolar Isoleucine. Alanine at this location is absolutely conserved across ~70 vertebrate species for which we have data. This variant is not present in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. However, two other missense variants at this location are present: Ala749Val (3 Latino individuals) and Ala749Thr (3 Latino individuals). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. Of note, our patient’s ancestry is Latino.

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