Submissions for variant NM_170707.4(LMNA):c.1445G>A (p.Arg482Gln)

gnomAD frequency: 0.00001  dbSNP: rs11575937

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041318	SCV000065011	pathogenic	Laminopathy	2019-04-05	criteria provided, single submitter	clinical testing	The p.Arg482Gln variant in LMNA has been reported in at least 20 individuals with Dunnigan-type familial partial lipodystrophy (FPLD) and segregated with disease in more than 40 affected family members from at least 8 families (Cao 2000, Hegel 2000, Speckman 2000, Vigouroux 2000, Ludtke 2005, Gambineri 2008, Mory 2012, Wiltshire 2013, Lewandowski 2015). Other clinical laboratories have reported this variant in ClinVar (Variation ID 14486). This variant has also been identified in 1/111632 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs11575937). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. Transgenic mice with the p.Arg482Gln variant of LMNA have a phenotype consistent FPLD (Wojtanik 2009). In summary, this variant meets criteria to be classified as pathogenic for FPLD in an autosomal dominant manner based on presence in multiple affected individuals, segregation studies, low frequency in the general population and in vivo functional studies. The ACMG/AMP Criteria applied: PS4, PP1_strong, PM2, PS3_moderate (Richards 2015).
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000057299	SCV000510952	pathogenic	not provided	2017-01-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459624	SCV000548869	pathogenic	Charcot-Marie-Tooth disease type 2	2024-09-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 482 of the LMNA protein (p.Arg482Gln). This variant is present in population databases (rs11575937, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal recessive Emery-Dreifuss muscular dystrophy (EDMD) and autosomal dominant familial lipodystrophy type 2 (FLPD2) (PMID: 10587585, 10999791, 19418082, 19859838, 20130076, 20625965, 23313286, 26662654). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14486). 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: 19201734, 20130076). For these reasons, this variant has been classified as Pathogenic.
Translational Genomics Laboratory, University of Maryland School of Medicine	RCV000754814	SCV000882464	pathogenic	Monogenic diabetes	2017-12-07	criteria provided, single submitter	clinical testing	The c.1445G>A variant in codon 482 (exon 8 of the RefSeq gene) of the Lamin A/C gene, LMNA, results in the substitution of Arginine to Glutamine. Mutations in the LMNA gene have been found to cause multiple disorders, collectively known as A-type laminopathies, that have overlapping signs and symptoms (23853504, 20074070, OMIM, 16364671). A-type laminopathies include familial partial lipodystrophy type 2 (FPLD2, also called familial partial lipodystrophy, Dunnigan type), Limb-Girdle muscular dystrophy type 1B, Emery-Dreifuss muscular dystrophy (EDMD), Charcot-Marie-Tooth type 2B1 disease, Hutchinson-Gilford progeria, Heart-hand syndrome, Slovenian type, mandibuloacral dysplasia, Malouf syndrome, and familial dilated cardiomyopathy (23853504, 20074070, OMIM). To date, no clear genotype-phenotype correlations have been identified (23853504, 20074070). The c.1445G>A variant has been identified in multiple individuals over multiple generations in families with clinical diagnoses of FPLD2 (22700598, 10868844, 10999845, 10587585, 10739751, 10655060). This variant was also found in the homozygous state in an individual with FPLD2 and autosomal recessive-EDMD (23313286). A different amino acid change at codon 482, Arg482Trp, has also been shown to segregate with FPLD2 (23853504, 22700598, 10999845, 10739751, 10655060). Approximately 75% of patients with FPLD2 have a mutation at Arg482, making it a mutational hotspot for FPLD2 (16364671). Multiple lines of computational evidence (SIFT, LRT, MutationTaster, FATHMM, MetaSVM, MetalR, GERP, CADD) predict the c.1445G>A variant is probably damaging to the protein structure, function, or protein-protein interaction. Indeed, functional studies of the Arg482Gln mutant protein, as well as the Arg482Trp protein, demonstrated a failure of adipocyte cell differentiation (16415042). A transgenic mouse harboring the Arg482Gln mutation recapitulates the FPLD2 phenotype and studies confirmed a lack of adipocyte renewal (19201734). ACMG criteria = PS3, PS4, PP1-strong, PM1, PM5, PP3
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000057299	SCV000885655	pathogenic	not provided	2017-08-11	criteria provided, single submitter	clinical testing	The LMNA c.1445G>A, p.Arg482Gln variant (rs11575937) has been reported in multiple families with familial partial lipodystrophy (Dunnigan-type) (Cao 2000, Drac 2010, Gamberini 2008, Hegele 2000, Hegele 2000b, Imachi 2009, Ludtke 2005, Shackleton 2000, Speckman 2000, Vigouroux 2000), and co-segregated with affected individuals (Cao 2000, Hegele 2000, Speckman 2000). Other missense variants at this position (p.Arg482Trp and p.Arg482Leu) have also been implicated in familial partial lipodystrophy (Hegele 2000b, Shackleton 2000, Speckman 2000, Vigouroux 2000). The variant protein appears to have no significant impact on the structural integrity of the nucleus, but appears to decrease Lamin B2 expression (Zwerger 2013). Transgenic mice expressing the human variant protein shows increase blood insulin levels, reduced insulin sensitivity, and impaired adipocyte differentiation, consistent with the clinical phenotypes in patients (Wojtanik 2009). The p.Arg482Gln variant is listed as pathogenic in ClinVar (Variation ID: 14486), and observed once in the Exome Variant Server (1/13006 alleles) and Genome Aggregation Database (1/246132 alleles). Based on the above information, the variant is classified as pathogenic. References: Cao H et al. Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet. 2000; 9(1):109-12. Gambineri A et al. Monogenic polycystic ovary syndrome due to a mutation in the lamin A/C gene is sensitive to thiazolidinediones but not to metformin. Eur J Endocrinol. 2008; 159(3):347-53. Hegele R et al. Association between nuclear lamin A/C R482Q mutation and partial lipodystrophy with hyperinsulinemia, dyslipidemia, hypertension, and diabetes. Genome Res. 2000; 10(5):652-8. Hegele R et al. Heterogeneity of nuclear lamin A mutations in Dunnigan-type familial partial lipodystrophy. J Clin Endocrinol Metab. 2000b; 85(9):3431-5. Imachi H et al. A case of Dunnigan-type familial partial lipodystrophy (FPLD) due to lamin A/C (LMNA) mutations complicated by end-stage renal disease. Endocrine. 2009; 35(1):18-21. Ludtke A et al. Hepatic steatosis in Dunnigan-type familial partial lipodystrophy. Am J Gastroenterol. 2005; 100(10):2218-24. Shackleton S et al. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet. 2000; 24(2):153-6. Speckman R et al. Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C. Am J Hum Genet. 2000; 66(4):1192-8. Vigouroux C et al. Lamin A/C gene: sex-determined expression of mutations in Dunnigan-type familial partial lipodystrophy and absence of coding mutations in congenital and acquired generalized lipoatrophy. Diabetes. 2000; 49(11):1958-62. Wojtanik K et al. The role of LMNA in adipose: a novel mouse model of lipodystrophy based on the Dunnigan-type familial partial lipodystrophy mutation. J Lipid Res. 2009; 50(6):1068-79. Zwerger M et al. Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo-cytoskeletal coupling. Hum Mol Genet. 2013; 22(12):2335-49.
Fulgent Genetics, Fulgent Genetics	RCV000763258	SCV000893895	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; Lethal tight skin contracture syndrome; Congenital muscular dystrophy due to LMNA mutation; Emery-Dreifuss muscular dystrophy 3, autosomal recessive	2018-10-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000015575	SCV001428676	pathogenic	Familial partial lipodystrophy, Dunnigan type	2022-05-30	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PS4,PM5_STR,PM1,PM2_SUP,PP3
Institute of Human Genetics, University of Leipzig Medical Center	RCV001822996	SCV002072535	pathogenic	Dilated cardiomyopathy 1A	2022-01-12	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS3, PS4, PM5_STR, PM1, PM2_SUP, PP3
Neuberg Centre For Genomic Medicine, NCGM	RCV000015575	SCV002073295	pathogenic	Familial partial lipodystrophy, Dunnigan type		criteria provided, single submitter	clinical testing	The missense variant p.R482Q in LMNA (NM_170707.4) has been previously reported in individuals with familial partial lipodystrophy type 2 and is a mutational hot spot for the same(Jacob KN et al).Mice models are consistent with a phenotype of FPL D (Wojtanik 2009).It has been submitted to ClinVar as Pathogenic .The missense variant c.1445G>A (p.R482Q) in LMNA (NM_170707.4) is not observed in the large population cohorts of the gnomAD and 1000 Genomes datasets (Exome Aggregation Consortium et al., 2016; 1000 Genomes Consortium et al., 2015)The p.R482Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R482Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 482 of LMNA is conserved in all mammalian species. The nucleotide c.1445 in LMNA is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000057299	SCV002501701	pathogenic	not provided	2021-12-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000057299	SCV002513142	pathogenic	not provided	2022-05-06	criteria provided, single submitter	clinical testing	Observed in apparent homozygous state in one individual with generalized lipodystrophy and Emery-Dreifuss muscular dystrophy in published literature (Wiltshire et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Transgenic mice harboring this variant develop a syndrome that resembles many of the features of human familial partial lipodystrophy (Wojtanik et al., 2009); Reported as pathogenic by several other clinical laboratories in ClinVar (ClinVar Variant ID# 14486; ClinVar); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30275911, 16181372, 10999845, 22700598, 26662654, 28641778, 17893350, 29578370, 19859838, 25637381, 23427149, 10999791, 20130076, 11792809, 19201734, 23313286, 20625965, 24375749, 19418082, 10587585, 12647844, 28679633, 25741868, 18728124, 10739751, 19011997, 12524233, 28663758, 30165155, 31194872, 28199729, 27485410, 28450900, 11136544, 11078466, 10655060, 10810087, 31836692, 31447099, 33502018, 32041611, 16415042, 10939567)
Ambry Genetics	RCV002390111	SCV002700255	pathogenic	Cardiovascular phenotype	2024-11-13	criteria provided, single submitter	clinical testing	The p.R482Q pathogenic mutation (also known as c.1445G>A), located in coding exon 8 of the LMNA gene, results from a G to A substitution at nucleotide position 1445. The arginine at codon 482 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been detected in many unrelated individuals with familial partial lipodystrophy (FPLD) and segregated with FPLD several families (Cao H et al. Hum Mol Genet, 2000 Jan;9:109-12; Shackleton S et al. Nat Genet, 2000 Feb;24:153-6; Gambineri A et al. Eur J Endocrinol, 2008 Sep;159:347-53; Boschmann M et al. J Clin Endocrinol Metab, 2010 Apr;95:1634-43; Lewandowski KC et al. Endokrynol Pol, 2015;66:550-4; Akinci B et al. Metabolism, 2017 07;72:109-119; Kwapich M et al. Diabetes Metab, 2019 09;45:382-389; Sekizkardes H et al. J Clin Endocrinol Metab, 2019 08;104:3068-3076). This mutation has also been detected in the homozygous state in siblings reported to have atypical autosomal recessive Emery-Dreifuss muscular dystrophy (Wiltshire KM et al. Neuromuscul Disord, 2013 Mar;23:265-8). In addition, a transgenic mouse model expressing this mutation recapitulated FPLD phenotype (Wojtanik KM et al. J Lipid Res, 2009 Jun;50:1068-79). This amino acid position is highly conserved through mammals. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000057299	SCV005413796	pathogenic	not provided	2023-08-29	criteria provided, single submitter	clinical testing	PP1_strong, PP4, PM1, PM2, PM5, PS3, PS4
All of Us Research Program, National Institutes of Health	RCV004806012	SCV005427711	uncertain significance	Primary dilated cardiomyopathy	2024-03-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 482 of the lamin A/C proteins. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been shown to cause partial lipodystrophy phenotype in a transgenic mouse model (PMID: 19201734). This variant has been reported in many individuals affected with familial partial lipodystrophy (PMID: 10587585, 10999791, 19418082, 19859838, 20130076, 20625965, 26662654, 30165155, 31194872, 33803652, 34340952, 34865644, 35291351, 37679847) and in individuals affected with Emery-Dreifuss muscular dystrophy (PMID: 23313286). However, this variant has not been reported in individuals affected with cardiomyopathy in the literature. This variant has been identified in 1/246132 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 familial partial lipodystrophy (ClinVar variation ID: 14486).
OMIM	RCV000015575	SCV000035840	pathogenic	Familial partial lipodystrophy, Dunnigan type	2013-03-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057299	SCV000088412	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000015575	SCV000190315	pathogenic	Familial partial lipodystrophy, Dunnigan type	2014-06-01	no assertion criteria provided	research
OMIM	RCV000190399	SCV000243941	pathogenic	Emery-Dreifuss muscular dystrophy 3, autosomal recessive	2013-03-01	no assertion criteria provided	literature only
Color Diagnostics, LLC DBA Color Health	RCV001179839	SCV001344626	uncertain significance	Cardiomyopathy	2023-10-05	flagged submission	clinical testing	This missense variant replaces arginine with glutamine at codon 482 of the lamin A/C proteins. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been shown to cause partial lipodystrophy phenotype in a transgenic mouse model (PMID: 19201734). This variant has been reported in many individuals affected with familial partial lipodystrophy (PMID: 10587585, 10999791, 19418082, 19859838, 20130076, 20625965, 26662654, 30165155, 31194872, 33803652, 34340952, 34865644, 35291351, 37679847) and in individuals affected with Emery-Dreifuss muscular dystrophy (PMID: 23313286). However, this variant has not been reported in individuals affected with cardiomyopathy in the literature. This variant has been identified in 1/246132 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 familial partial lipodystrophy (ClinVar variation ID: 14486).
Genetic Services Laboratory, University of Chicago	RCV000015575	SCV002070468	pathogenic	Familial partial lipodystrophy, Dunnigan type	2020-11-12	no assertion criteria provided	clinical testing	DNA sequence analysis of the LMNA gene demonstrated a sequence change, c.1445G>A, in exon 8 that results in an amino acid change, p.Arg482Gln. This sequence change has been described in the EXAC database with a low population frequency of 0.001% (dbSNP rs11575937). The p.Arg482Gln variant in LMNA has been reported in multiple families with Dunnigan-type familial partial lipodystrophy (FPLD) and co-segregated with affected individuals (PMIDs: 10587585, 10999791, 19418082, 19859838, 20130076, 20625965, 26662654). Transgenic mice expressing the p.Arg482Gln variant showed increase blood insulin levels, reduced insulin sensitivity, and impaired adipocyte differentiation, consistent with the clinical phenotypes observed in patients (PMID: 19201734). Furthermore, other missense changes at this same position (p.Arg482Trp and p.Arg482Leu) have also been implicated in familial partial lipodystrophy (PMIDs: 10655060, 10739751).
PreventionGenetics, part of Exact Sciences	RCV004532361	SCV004121213	pathogenic	LMNA-related disorder	2024-08-07	no assertion criteria provided	clinical testing	The LMNA c.1445G>A variant is predicted to result in the amino acid substitution p.Arg482Gln. This variant has been reported in the homozygous state in two Hutterite siblings that presented with an atypical Emery-Dreifuss muscular dystrophy and in the heterozygous state in other family members with familial partial lipodystrophy and abnormal lipid profiles (Wiltshire et al. 2013. PMID: 23313286). Of note, the authors tested for the c.1445G>A variant in 482 Dariusleut and Leherleut Hutterites in Alberta and found the overall carrier frequency to be 1.45%. In addition, this variant in the heterozygous state has been reported in several unrelated families of other ethnicities to be causative for familial partial lipodystrophy in an autosomal dominant manner (Cao and Hegele. 2000. PubMed ID: 10587585; Hegele et al. 2000. PubMed ID: 10999791; Speckman et al. 2000. PubMed ID: 10739751; Vasandani et al. 2022. PubMed ID: 36397776; http://www.LOVD.nl/LMNA). This variant has not been reported in a large population database, indicating this variant is rare. In summary, the c.1445G>A variant is pathogenic for a spectrum of laminopathies in both the heterozygous and homozygous state.