Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000057457 | SCV000292943 | likely pathogenic | not provided | 2017-05-12 | criteria provided, single submitter | clinical testing | The Y259X variant in the LMNA gene has been reported in association with limb gridle muscular dystrophy and cardiomyopathy (Muchir et al., 2003; van Tintelen et al., 2007; van Spaendonck-Zwarts et al., 2013). Y259X was first reported in the homozygous state in a newborn who died at birth and in the heterozygous state in his maternal grandmother who had a diagnosis of limb girdle muscular dystrophy and bradycardia (Muchir et al., 2003) Y259X was subsequently identified in a female with a first-degree AV block and supraventricular tachycardias who was found to be related to the family reported by Muchir et al. (van Tintelen et al., 2007). Of 10 patients from this family, 5 carried pacemakers, however, a diagnosis of DCM was not mentioned in any of the patients (van Tintelen et al., 2007). Nevertheless, Y259X has been reported in one individual with DCM with possible neuromuscular involvement (van Spaendonck-Zwarts et al., 2013).Functional studies in fibroblast cells showed a reduction in lamin A and C expression when Y259X was in the heterozygous state and a complete absence of expression in the homozygous state (Muchir et al., 2003). A truncated protein product was not observed in any of the fibroblast cells harboring the Y259X variant suggesting haploinsufficiency is the likely disease mechanism (Muchir et al., 2003). In another study, Y259X in the homozygous state was shown to cause nuclear rupture and loss of cellular compartmentalization (De Vos et al., 2011). Additionally, other nonsense variants in the LMNA gene have been reported in HGMD in association with DCM (Stenson P et al., 2014). Furthermore, the Y259X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on currently available evidence, Y259X is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded. |
| OMIM | RCV000015605 | SCV000035870 | pathogenic | Emery-Dreifuss muscular dystrophy 2, autosomal dominant | 2005-01-25 | no assertion criteria provided | literature only | |
| Epithelial Biology; Institute of Medical Biology, |
RCV000057457 | SCV000088571 | not provided | not provided | no assertion provided | not provided |