ClinVar Miner

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

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Total submissions: 9
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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

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