Submissions for variant NM_002230.4(JUP):c.266T>C (p.Met89Thr)

gnomAD frequency: 0.00001  dbSNP: rs542745694

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000707335	SCV000836427	uncertain significance	Naxos disease; Arrhythmogenic right ventricular dysplasia 12	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 89 of the JUP protein (p.Met89Thr). This variant is present in population databases (rs542745694, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with JUP-related conditions. ClinVar contains an entry for this variant (Variation ID: 583093). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193378	SCV001362156	likely benign	not specified	2019-11-05	criteria provided, single submitter	clinical testing	Variant summary: JUP c.266T>C (p.Met89Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 232480 control chromosomes, predominantly at a frequency of 0.00034 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 34 fold of the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.266T>C in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV000786330	SCV001764688	uncertain significance	not provided	2022-08-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002424726	SCV002743865	likely benign	Cardiovascular phenotype	2021-08-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786330	SCV000925105	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.Met89Thr (M89T; c.266T>C) in exon 3 of the JUP gene (NM_002230.2; ENST00000393931.7) Chromosome position: 17:39925872 A / G Based on the information reviewed below, including lack of case data, we classify it as a Variant of Uncertain Signficance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. Because of its increased prevalence among individuals with Latino ancestry (like our patient), we suspect that it is more likely to be benign. Of note, the JUP gene is associated with ARVC, which is not our patient’s phenotype. This variant has not been reported in the literature in association with disease. This is a nonconservative amino acid change, resulting in the replacement of a nonpolar Methionine with a polar Threonine. Methionine at this location is highly conserved across vertebrate species, although it is replaced by another nonpolar amino acid in a few species. There are no missense variants within 10 residues currently listed as Pathogenic or Likely Pathogenic in ClinVar, which suggests this region of the protein may be tolerant of change. This variant was reported in 12/113,726 individuals (MAF 0.005%) in the gnomAD database, which includes ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 10/15,634 Latino individuals (for the highest allele frequency: 0.032%), and 2/51,540 non-Finnish Europeans (MAF 0.002%). 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.