Submissions for variant NM_170707.4(LMNA):c.1444C>T (p.Arg482Trp)

gnomAD frequency: 0.00001  dbSNP: rs57920071

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000015579	SCV000247852	pathogenic	Familial partial lipodystrophy, Dunnigan type	2014-11-14	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001174239	SCV001337368	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Invitae	RCV001235764	SCV001408468	pathogenic	Charcot-Marie-Tooth disease type 2	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 482 of the LMNA protein (p.Arg482Trp). This variant is present in population databases (rs57920071, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant familial partial lipodystrophy (PMID: 19622949, 25885670). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14489). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 19220582). This variant disrupts the p.Arg482 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10587585, 10999791, 19418082, 19859838, 20130076, 20625965, 26662654). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248961	SCV001422760	pathogenic	Familial partial lipodystrophy	2020-01-22	criteria provided, single submitter	curation	The p.Arg482Trp variant in LMNA has been reported in at least 12 European individuals with familial partial lipodystrophy, segregated with disease in at least 7 affected relatives from 2 families (PMID: 15531479, 10655060,11344241), and has been identified in 0.0009% (1/113640) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs57920071). This variant has also been reported in ClinVar as pathogenic (Variation ID: 14489). In vitro functional studies provide some evidence that the p.Arg482Trp variant may slightly impact protein function (PMID: 25524705). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic and one pathogenic variant, resulting in a different amino acid change at the same position, p.Arg482Leu and p.Arg482Gln, have been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 10655060, 14597414, 19201734, 23313286, 10587585, 20130076, 28492532 /Variation ID: 14490 and 14486). In summary, this variant meets criteria to be classified as pathogenic for familial partial lipodystrophy in an autosomal dominant manner based on cosegregation with disease in multiple affected families and the prevalence of this variant in many affected individuals. ACMG/AMP Criteria applied: PP1_strong, PS4_moderate, PM5, PM2, PP3, PS3_supporting (Richards 2015).
Ambry Genetics	RCV001266075	SCV001444247	pathogenic	Inborn genetic diseases	2018-12-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000057298	SCV001784724	pathogenic	not provided	2019-10-15	criteria provided, single submitter	clinical testing	Recurrent pathogenic variant that has been reported in the heterozygous state in multiple individuals with partial lipodystrophy (Shackleton et al., 2000); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Multiple functional studies demonstrate that the R482W variant impairs the function of several lamin A interacting genes involved in adipogenesis and lipid metabolism (Vadrot et al., 2015; Oldenburg et al., 2014); This variant is associated with the following publications: (PMID: 32041611, 31383942, 30954027, 29704234, 31194872, 30165155, 29108996, 16459536, 19622949, 17524034, 12524233, 28641778, 27841971, 29438482, 28751304, 27504462, 24002959, 26976018, 12669268, 26724531, 10655060, 24375749, 14749366, 11792809, 19220582, 11344241, 20130076, 25524705, 24108105, 23427149, 18396274, 25885670, 23846499, 21989830, 19574635, 29578370, 14510863, 26027246, 26756202)
Revvity Omics, Revvity	RCV000057298	SCV002017165	pathogenic	not provided	2021-02-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390112	SCV002701519	pathogenic	Cardiovascular phenotype	2018-11-27	criteria provided, single submitter	clinical testing	The p.R482W pathogenic mutation (also known as c.1444C>T), located in coding exon 8 of the LMNA gene, results from a C to T substitution at nucleotide position 1444. The arginine at codon 482 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration is a recurrent mutation that has been detected in numerous individuals with familial partial lipodystrophy (FPLD) and has been shown to segregate with disease in multiple families (Peters JM et al. Nat. Genet., 1998 Mar;18:292-5; Hegele RA et al. J. Clin. Endocrinol. Metab., 2000 Sep;85:3431-5; Speckman RA et al. Am. J. Hum. Genet., 2000 Apr;66:1192-8; Vigouroux C et al. Diabetes, 2000 Nov;49:1958-62; Schmidt HH et al. J. Clin. Endocrinol. Metab., 2001 May;86:2289-95; Vantyghem MC et al. J. Clin. Endocrinol. Metab., 2004 Nov;89:5337-46; Keller J et al. Obstet Gynecol, 2009 Aug;114:427-31; Nabrdalik K et al. Endokrynol Pol, 2013;64:306-11; Akinci B et al. Metab. Clin. Exp., 2017 07;72:109-119). Other alterations in the same codon, p.R482Q and p.R482L, have also been described in FPLD patients (Shackleton S et al. Nat. Genet., 2000 Feb;24:153-6). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002482872	SCV002793126	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	2022-04-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003934834	SCV004754078	pathogenic	LMNA-related condition	2023-10-20	criteria provided, single submitter	clinical testing	The LMNA c.1444C>T variant is predicted to result in the amino acid substitution p.Arg482Trp. This variant has been reported in the heterozygous state in many unrelated individuals and is the most common causative variant for familial partial lipodystrophy in the LMNA gene (Shackleton et al. 2000. PubMed ID: 10655060; Cao and Hegele. 2000. PubMed ID: 10587585; Belo et al. 2015. PubMed ID: 25885670; Vadrot et al. 2015. PubMed ID: 25524705; Vasandani et al. 2022. PubMed ID: 36397776). Functional studies indicate the p.Arg482Trp variant in the LMNA protein impairs the transcriptional activity of SREBP1 which plays a key role in lipid metabolism and adipocyte differentiation (Vadrot et al. 2015. PubMed ID: 25524705). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-156106775-C-T). Based on the collective evidence, this variant is interpreted as pathogenic.
OMIM	RCV000015579	SCV000035844	pathogenic	Familial partial lipodystrophy, Dunnigan type	2001-05-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057298	SCV000088411	not provided	not provided		no assertion provided	not provided