Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001088249 | SCV000677002 | likely benign | Long QT syndrome 6 | 2023-10-03 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002415515 | SCV002678828 | benign | Cardiovascular phenotype | 2023-10-13 | criteria provided, single submitter | clinical testing | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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. |
| New York Genome Center | RCV002467562 | SCV002764380 | uncertain significance | Atrial fibrillation, familial, 4; Long QT syndrome 6 | 2021-10-05 | criteria provided, single submitter | clinical testing | |
| Cardiovascular Biomedical Research Unit, |
RCV000058378 | SCV000089898 | not provided | Congenital long QT syndrome | no assertion provided | literature only | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. | |
| CSER _CC_NCGL, |
RCV000148520 | SCV000190232 | uncertain significance | Long QT syndrome | 2014-06-01 | no assertion criteria provided | research | |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786140 | SCV000924807 | uncertain significance | not provided | 2017-04-21 | no assertion criteria provided | provider interpretation | This variant was found in a 14 yo male with a history of V-fib cardiac arrest, WPW, atrial fibrillation, and LVNC found on cardiac MRI. He had genetic testing with the Invitae laboratory. The following 124 genes associated with heritable arrhythmia syndromes and cardiomyopathies were evaluated for sequence changes and exonic deletions/duplications: ABCC9, ACADVL, ACTC1, ACTN2, AGL, AKAP9, ALMS1, ANK2, ANKRD1, BAG3, CACNA1C, CACNA2D1, CACNB2, CALM1, CALM2, CALM3, CALR3, CASQ2, CAV1, CAV3, CHRM2, CPT2, CRYAB, CSRP3, CTF1, CTNNA3, DES, DMD, DNAJC19, DOLK, DSC2, DSG2, DSP, DTNA, ELAC2, EMD, EYA4, FHL1, FHL2, FKRP, FKTN, FLNC, GAA, GATA4, GATA6, GATAD1, GJA1, GJA5, GLA, GPD1L, HCN4, ILK, JPH2, JUP, KCNA5, KCND3, KCNE1, KCNE2, KCNE3, KCNE5, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNK3, KCNQ1, LAMA4, LAMP2, LDB3, LMNA, LRRC10, MTO1, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYL4, MYLK2, MYOM1, MYOZ2, MYPN, NEBL, NEXN, NKX2-5, NKX2-6, NPPA, PDLIM3, PKP2, PLEKHM2, PLN, PRDM16, PRKAG2, RAF1, RANGRF, RBM20, RYR2, SCN10A, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SGCD, SLC22A5, SLMAP, SNTA1, TAZ, TBX5, TCAP, TGFB3, TMEM43, TMEM70, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRDN, TRPM4, TTN, TTR, TXNRD2, VCL. The following gene was evaluated for sequence changes only: SDHA. One variant was reported: p.Arg27His (R27H; c.80G>A) in exon 2 of the KCNE2 gene (NM_172201.1; ENST00000290310) Chromosome location: 21:35742857 G / A Based on the information reviewed below, including its appreciable frequency in the broader population, particularly in people with African ancestry such as our patient, we classify it as a Variant of Uncertain Significance (VUS), probably benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing. This variant has previously been reported in two individuals suspected to have LQTS. Their ethnicity is not reported. There is no published segregation data. The variant was reported in 1 individual in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009, PMID: 19716085). Of note, there is no phenotype data on this cohort confirming a diagnosis of LQTS, and genetic testing had a low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT). There is also a lack of clarity regarding which variants were seen alongside another variant (9% of the cohort had multiple variants). The Arg27His variant was also reported by Sauer and Marc-Aurele (2016) in a 19-day-old female neonate with documented VF and a QTc of 465 msec; the baby also had a second variant in KCNE2, Ile20Asn (which is absent from gnomAD and not yet reported to ClinVar by any genetic testing lab), apparently in trans—given that her mother tested positive only for Arg27His (PMID: 27465075). Her testing was done at Familion. This is a conservative amino acid change, resulting in the replacement of a positively-charged Arginine with a positively-charged Histidine. Arginine at this location is fairly highly conserved across ~100 vertebrate species, although Histidine is the default amino acid in at least 2 species, suggesting that this missense change is tolerated (in two other species it is a Serine or a Glutamine). There are no missense variants at nearby residues (+/- 10) currently listed in ClinVar as Likely Pathogenic or Pathogenic. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25". These predictions have not been confirmed by published functional studies. This variant was reported online in 24 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 20/12,012 individuals with African ancestry like our patient (for the highest allele frequency: 0.08%), 3 Latinos, and 1 non-Finnish European. Overall MAF 0.009%. The variant is almost 10x more frequent among people with African ancestry than any other ethnicity. 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. Another variant at the same codon (Arg27Cys) has been reported in the literature as associated with atrial fibrillation. Yang et al. (2004) reported Arg27Cys in 2/28 Chinese probands with AF. (PMID:15368194). Koo et al. (2006) reported it as a polymorphism with MAF estimated at 0.38% in healthy Chinese volunteers (n=265; 1 volunteer had the variant) from Singapore (PMID:16487223). Of note, it is present in 37 individuals in gnomAD, with the highest MAF of 0.095% in East Asians. (Overall MAF 0.013%.) Blueprint Genetics has reported it to ClinVar as a VUS. There is also one Caucasian individual in gnomAD with the variant Arg27Ser. Therefore, it appears that variation at this codon is fairly common, which argues against pathogenicity. |