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

gnomAD frequency: 0.00004  dbSNP: rs57520892

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000057326	SCV000233098	pathogenic	not provided	2014-06-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000057326	SCV000234705	pathogenic	not provided	2021-12-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: failure to restore p16ink4A/pRB pathway signaling, increased sensitivity to ionizing radiation, and destabilization of heterochromatin-associated proteins (Filesi et al., 2005; Nitta et al., 2006; di Masi et al., 2008); 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: 23891399, 24375749, 25637381, 18604166, 12075506, 14627682, 12788894, 16046620, 19764019, 28663758, 25823658, 19084400, 17848409, 31589614, 32041611, 32376792, 34135346, 33422685, 10939567, 33038109, 15473259, 29854317, 25324471, 16809772, 10080180, 31383942)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000555364	SCV000657803	pathogenic	Charcot-Marie-Tooth disease type 2	2024-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 527 of the LMNA protein (p.Arg527His). This variant is present in population databases (rs57520892, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive mandibuloacral dysplasia (PMID: 12075506, 14627682). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14499). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LMNA function (PMID: 12075506, 18604166, 25324471, 25823658). 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
Baylor Genetics	RCV000015591	SCV001522190	pathogenic	Mandibuloacral dysplasia with type A lipodystrophy	2020-01-09	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000057326	SCV002017155	pathogenic	not provided	2020-10-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399328	SCV002709534	uncertain significance	Cardiovascular phenotype	2024-11-19	criteria provided, single submitter	clinical testing	The p.R527H variant (also known as c.1580G>A), located in coding exon 9 of the LMNA gene, results from a G to A substitution at nucleotide position 1580. The arginine at codon 527 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in several homozygous or compound heterozygous individuals with autosomal recessive mandibuloacral dysplasia (MAD), and individuals with MAD plus overlapping laminopathy features and atypical myopathies (Shen JJ et al. J. Med. Genet., 2003 Nov;40:854-7; Lombardi F et al. J. Clin. Endocrinol. Metab., 2007 Nov;92:4467-71; Garavelli L et al. Am. J. Med. Genet. A, 2009 Oct;149A:2258-64; Sakka et al. Eur J Med Genet, 2021 Feb;64:104138; Jéru I et al. Genes (Basel), 2021 Sep;12; Turkyilmaz A et al. Clin Dysmorphol. 2021 Jan;30(1):10-16). Heterozygous carrier family members and healthy population cohort participants have been reported to be unaffected with MAD or other laminopathy-related phenotypes (Dron JS et al. BMC Med Genomics, 2020 02;13:23; Lacaze P et al. NPJ Genom Med, 2021 Jun;6:51; Sakka et al. Eur J Med Genet, 2021 Feb;64:104138). In assays testing LMNA function, this variant showed a functionally abnormal result (Novelli G et al. Am. J. Hum. Genet., 2002 Aug;71:426-31; Evangelisti C et al. Oncotarget, 2015 Apr;6:7424-37; di Masi A et al. Cell Cycle, 2008 Jul;7:2030-7). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of mandibuloacral dysplasia (MAD) when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant laminopathy-related phenotypes is unclear.
All of Us Research Program, National Institutes of Health	RCV003996101	SCV004819819	uncertain significance	Primary dilated cardiomyopathy	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 527 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). In a transgenic mouse model, this variant has been associated with phenotypes relevant for mandibuloacral dysplasia type A syndrome while muscle phenotypes are normal (PMID: 33458588). Fibroblast cell cultures from the transgenic mice displayed nuclear envelope aberrations, accumulation of the lamin A precursor protein, proliferation, and senescence rate defects (PMID: 33458588). Another functional study has shown that cells from a homozygous carrier show abnormal nuclear morphology, while cells from a heterozygous carrier show normal nuclear morphology (PMID: 12075506). Other functional studies have suggested that this variant may increase sensitivity to ionizing radiation (PMID:18604166), affect DNA synthesis (PMID 25324471) and fail to downregulate TGFbeta-2 secretion (PMID: 25823658). This variant has been associated with autosomal recessive mandibuloacral dysplasia and Charcot-Marie-Tooth disease in several families and has been reported in the homozygous or compound heterozygous states in multiple affected individuals (PMID: 12075506, 14627682, 25286833, 32376792, 33038109, 33422685, 34680903, Xu et al. 2019 doi: 10.3969/j.issn.1000-3606.2019.09.010). Most affected carriers showed no signs of cardiac involvement except for one individual who was also affected with dilated cardiomyopathy (PMID: 33422685). Heterozygous parents were reported to be healthy. This variant has also been identified in 10/250812 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy, although it is known to cause autosomal recessive mandibuloacral dysplasia and Charcot-Marie-Tooth disease (ClinVar variation ID: 14499).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000148607	SCV004848697	pathogenic	Mandibuloacral dysplasia	2019-02-08	criteria provided, single submitter	clinical testing	The p.Arg527His variant in LMNA has been reported in the homozygous or compound heterozygous state in 10 individuals with mandiculoacral dysplasia (MAD) and segregated with disease in 5 affected individuals from 4 families (Novelli 2002, Shen 2003, Simha 2003, Garavelli 2009). It has also been identified in 6/31826 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org), however, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 14499). In vitro functional studies support an impact on protein function (Novelli 2002, Amati 2004, Filesi 2005, Nitta 2006, Lombardi 2007, Meaburn 2007, di Masi 2008, Evangelisti 2015). Three additional variants involving this codon (p.Arg527) have been identified in individuals with MAD (Stenson 2017). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MAD. ACMG/AMP Criteria applied: PM3_VeryStrong, PS4, PM5_Strong, PP1_Strong, PS3_Moderate, BP4.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000015591	SCV005399150	pathogenic	Mandibuloacral dysplasia with type A lipodystrophy	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Missense variants have been reported to result in gain of function and dominant negative effects, and are associated with childhood-onset disease or skeletal muscle involvement while protein truncating variants have been reported to result in loss of function and haploinsufficiency, and are associated with the adult-onset disease, cardiac disorders or myopathy (PMID: 17377071). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance, mainly associated with Emery-Dreifuss muscular dystrophy and LMNA-related dilated cardiomyopathy (PMID: 20301609). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a condition (v2: 10 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (5 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated lamin tail domain (NCBI conserved domain]. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is a recurrent pathogenic variant associated with mandibuloacral dysplasia (MIM#248370) (MAD) and has been reported in at least ten homozygous or compound heterozygous in individuals with MAD (ClinVar; PMIDs: 14627682, 17848409, 28663758, 29557732). The association of this variant with cardiomyopathy is currently unclear (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005042058	SCV005678981	pathogenic	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy, Dunnigan type; Mandibuloacral dysplasia with type A lipodystrophy; Congenital muscular dystrophy due to LMNA mutation; Emery-Dreifuss muscular dystrophy 3, autosomal recessive; Restrictive dermopathy 2	2024-03-27	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
Color Diagnostics, LLC DBA Color Health	RCV001178367	SCV001342797	uncertain significance	Cardiomyopathy	2023-05-16	flagged submission	clinical testing	This missense variant replaces arginine with histidine at codon 527 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). In a transgenic mouse model, this variant has been associated with phenotypes relevant for mandibuloacral dysplasia type A syndrome while muscle phenotypes are normal (PMID: 33458588). Fibroblast cell cultures from the transgenic mice displayed nuclear envelope aberrations, accumulation of the lamin A precursor protein, proliferation, and senescence rate defects (PMID: 33458588). Another functional study has shown that cells from a homozygous carrier show abnormal nuclear morphology, while cells from a heterozygous carrier show normal nuclear morphology (PMID: 12075506). Other functional studies have suggested that this variant may increase sensitivity to ionizing radiation (PMID:18604166), affect DNA synthesis (PMID 25324471) and fail to downregulate TGFbeta-2 secretion (PMID: 25823658). This variant has been associated with autosomal recessive mandibuloacral dysplasia and Charcot-Marie-Tooth disease in several families and has been reported in the homozygous or compound heterozygous states in multiple affected individuals (PMID: 12075506, 14627682, 25286833, 32376792, 33038109, 33422685, 34680903, Xu et al. 2019 doi: 10.3969/j.issn.1000-3606.2019.09.010). Most affected carriers showed no signs of cardiac involvement except for one individual who was also affected with dilated cardiomyopathy (PMID: 33422685). Heterozygous parents were reported to be healthy. This variant has also been identified in 10/250812 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy, although it is known to cause autosomal recessive mandibuloacral dysplasia and Charcot-Marie-Tooth disease (ClinVar variation ID: 14499).