Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000057439 | SCV000576911 | likely pathogenic | not provided | 2023-08-24 | criteria provided, single submitter | clinical testing | Identified in an individual with DCM plus atrioventricular block; two out of three additional family members were also reportedly affected and had the familial variant (Pasotti et al., 2008); Identified in an extended family with 14 affected individuals, four of whom showed severe cardiomyopathy by early adulthood (Roncarati et al., 2013); all 14 affected family members were found to harbor the p.(K219T) variant but an additional missense variant in the TTN gene, p.(L4855F), was identified in the severely affected patients. Myocardial specimens from individuals who were doubly heterozygous for the familial LMNA and TTN variants showed increased nuclear length, sarcomeric disorganization, and myonuclear clustering compared to muscle samples from individuals who only carried the LMNA K219T variant. The authors suggest that in this particular family, the p.(L4855F) variant in the TTN gene may act as a modifier for familial DCM; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect using patient-derived cardiomyocytes with the p.(K219T) variant that show abnormal action potential and sodium channel properties as well as abnormal SCN5A expression (Salvarani et al., 2019); isogenic correction of the p.(K219T) mutation was able to restore INa properties and SCN5A expression; Published functional study suggests that patient fibroblasts carrying the p.(K219T) variant showed decreased nuclear localization (Ho et al., 2013); Published functional studies suggest a damaging effect as the p.(K219T) variant results in formation of aggregates and increased the bind affinity for LA/LB1 meshworks (Bhattacharjee et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35935653, 32719615, 30858397, 36899919, 31427369, 36503349, 34975533, 34408666, 33923914, 33803477, 35159226, 36704457, 35453731, 34887928, 32326823, 35163304, 35846372, 30764827, 32155092, 34768351, 36274847, 30425656, 18795223, 24860693, 31118417, 10939567, 23463027, 18926329, 28844980, 27182706, 27493940) |
| Epithelial Biology; Institute of Medical Biology, |
RCV000057439 | SCV000088553 | not provided | not provided | no assertion provided | not provided |