Submissions for variant NM_170707.4(LMNA):c.1583C>T (p.Thr528Met)

gnomAD frequency: 0.00001  dbSNP: rs57629361

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000057330	SCV000703215	uncertain significance	not provided	2016-11-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001182566	SCV001348060	uncertain significance	Cardiomyopathy	2020-03-12	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 528 of the lamin A/C proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes abnormal nuclei with aggregates (PMID: 22413764), nuclear rupture and loss of compartmentalization (PMID: 21831885). However, clinical relevance of these observations is not clear. This variant has been reported in an individual affected with non-valvular atrial fibrillation (PMID: 22413764), as well as in an individual affected with familial partial lipodystrophy (PMID: 28641778). This variant has also been reported in compound heterozygous state with other variants in the LMNA gene in individuals affected with Hutchinson-Gilford progeria syndrome (PMID: 16825282), familial partial lipodystrophy (PMID: 15298354, 29078011), or mandibuloacral dysplasia with type A lipodystrophy (Xiang et al., 2014). Heterozygous carriers of this variant in these families were reported to be unaffected. This variant has been identified in 2/214466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While this variant has been observed in multiple individuals affected with laminopathy, the available evidence is insufficient to determine the role of this variant in autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057330	SCV000088443	not provided	not provided		no assertion provided	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000057330	SCV001743048	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000057330	SCV001953784	uncertain significance	not provided		no assertion criteria provided	clinical testing