Submissions for variant NM_170707.4(LMNA):c.1580G>A (p.Arg527His) (rs57520892)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000057326	SCV000233098	pathogenic	not provided	2014-06-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000057326	SCV000234705	pathogenic	not provided	2018-11-14	criteria provided, single submitter	clinical testing	The R527H pathogenic variant in the LMNA gene has been reported multiple times in association with autosomal recessive mandibuloacral dysplasia (MAD) (Novelli et al., 2002; Shen et al., 2003; Simha et al., 2003; Lombardi et al., 2007; Garavelli et al., 2009). R527H has not been reported in association with a cardiomyopathy phenotype to our knowledge, and to date, heterozygous carriers of the R527H variant have not been reported to exhibit disease phenotype. However, R527H has been observed at GeneDx in the heterozygous state, in the absence of other pathogenic variants, in one individual diagnosed with dilated cardiomyopathy. The R527H variant is observed in 6/30986 (0.02%) alleles from individuals of Latino ancestry in large population cohorts (Lek et al., 2016). The R527H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Functional studies using fibroblasts from homozygous R527H MAD patients demonstrated that R527H results in an accumulation of unprocessed prelamin A, alters distribution of the lamin B receptor, and destabilizes two heterochromatin-associated proteins (Filesi et al., 2005). Finally, several missense variants in the same residue (R527C, R527L, R527P) have been reported in association with laminopathies (Cao et al., 2003; Scharner et al., 2013; Zwerger et al., 2013), supporting the functional importance of this region of the protein. In summary, R527H in the LMNA gene is interpreted as a pathogenic variant.
Invitae	RCV000555364	SCV000657803	pathogenic	Charcot-Marie-Tooth disease, type 2	2019-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 527 of the LMNA protein (p.Arg527His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs57520892, ExAC 0.05%). This variant has been reported to segregate with autosomal recessive mandibuloacral dysplasia in several families and has been reported in the homozygous state in multiple affected individuals (PMID: 12075506, 14627682). ClinVar contains an entry for this variant (Variation ID: 14499). Experimental studies have shown that this missense variant leads to abnormal nuclear morphology, altered cell cycle regulation and increased sensitivity to ionizing radiation (PMID: 12075506, 18604166, 25823658, 25324471). For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics Laboratory,London Health Sciences Centre	RCV001174240	SCV001337369	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Color	RCV001178367	SCV001342797	uncertain significance	Cardiomyopathy	2020-03-25	criteria provided, single submitter	clinical testing
OMIM	RCV000015591	SCV000035856	pathogenic	Mandibuloacral dysplasia with type A lipodystrophy	2009-10-01	no assertion criteria provided	literature only
OMIM	RCV000015592	SCV000035857	pathogenic	Mandibuloacral dysplasia with type A lipodystrophy, atypical	2009-10-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057326	SCV000088439	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000148607	SCV000190322	uncertain significance	Mandibuloacral dysplasia	2014-06-01	no assertion criteria provided	research