ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1445G>A (p.Arg482Gln) (rs11575937)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041318 SCV000065011 pathogenic Laminopathy 2016-10-04 criteria provided, single submitter clinical testing The p.Arg482Gln variant in LMNA has been reported in at least 20 individuals wit h Dunnigan-type familial partial lipodystrophy (FPLD) and segregated with diseas e in more than 40 affected family members from at least 8 families (Cao 2000, He gel 2000, Speckman 2000, Vigouroux 2000, Ludtke 2005, Gambineri 2008, Mory 2012, Wiltshire 2013, Lewandowski 2015). Other clinical laboratories have reported th is variant in ClinVar (Variation ID 14486). This variant has also been identifie d in 1/111632 European chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org; dbSNP rs11575937). Please note that for disease s with clinical variability, reduced penetrance, or recessive inheritance, patho genic variants may be present at a low frequency in the general population. Tran sgenic mice with the p.Arg482Gln variant of LMNA have a phenotype consistent FPL D (Wojtanik 2009). In summary, this variant meets criteria to be classified as p athogenic for FPLD in an autosomal dominant manner based on presence in multiple affected individuals, segregation studies, low frequency in the general populat ion and in vivo functional studies. 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
Invitae RCV000459624 SCV000548869 pathogenic Charcot-Marie-Tooth disease, type 2 2018-05-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 482 of the LMNA protein (p.Arg482Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs11575937, ExAC 0.002%). This variant has been reported in many individuals affected with familial lipodystrophy type 2 (FLPD2) and has been observed to segregate with the disease in several families (PMID: 10587585, 10999791, 19418082, 19859838, 20130076, 20625965, 26662654). This variant has also been reported in the homozygous state in individuals affected with autosomal recessive Emery-Dreifuss muscular dystrophy (EDMD) (PMID: 23313286). ClinVar contains an entry for this variant (Variation ID: 14486). Experimental studies have shown that this variant recapitulates the FLPD2 phenotype in a mouse model (PMID: 19201734). In addition, in vitro studies in muscle biopsies from individuals carrying this variant detected an imbalance between lipid oxidation and oxidative glucose metabolism (PMID: 20130076). For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000015575 SCV000595606 pathogenic Familial partial lipodystrophy 2 2013-02-08 criteria provided, single submitter clinical testing
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; Benign scapuloperoneal muscular dystrophy with cardiomyopathy; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy 2; Mandibuloacral dysostosis; Lethal tight skin contracture syndrome; Congenital muscular dystrophy, LMNA-related; Emery-Dreifuss muscular dystrophy 3, autosomal recessive 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000015575 SCV000035840 pathogenic Familial partial lipodystrophy 2 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 Medical Center RCV000148600 SCV000190315 pathogenic Partial lipodystrophy, Dunnigan 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

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