Submissions for variant NM_170707.4(LMNA):c.1751G>A (p.Arg584His)

gnomAD frequency: 0.00001  dbSNP: rs56657623

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041330	SCV000065023	uncertain significance	not specified	2019-06-28	criteria provided, single submitter	clinical testing	The p.Arg584His variant in LMNA has been identified in 3 individuals with familial partial lipodystrophy (FPLD), one of whom was a homozygote, and 1 individual with DCM and ventricular tachycardia (Vigoroux 2000, Hegele 2000, Mory 2012, LMM data). It has also been identified in 4/242954 chromosomes in gnomAD (https://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID #48049). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PM2.
GeneDx	RCV000057355	SCV000292602	uncertain significance	not provided	2020-11-23	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 48049; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31194872, 22700598, 28679633, 24623722, 18366013, 11078466, 10999845)
Invitae	RCV001065506	SCV001230465	likely pathogenic	Charcot-Marie-Tooth disease type 2	2024-01-31	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 584 of the LMNA protein (p.Arg584His). This variant is present in population databases (rs56657623, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of familial partial lipodystrophy (PMID: 10999845, 11078466, 22700598, 31194872, 33502018, 36397776). ClinVar contains an entry for this variant (Variation ID: 48049). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 24623722). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001184222	SCV001350162	uncertain significance	Cardiomyopathy	2018-12-10	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the actin binding domain of the LMNA protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in three individuals affected with familial partial lipodystrophy (PMID: 10999845, 11078466, 22700598). One of these individuals was a homozygote, and the proband's heterozygous parents did not appear to be affected (PMID: 22700598). This variant has been identified in 4/238564 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Genetic Services Laboratory, University of Chicago	RCV000041330	SCV002067341	uncertain significance	not specified	2019-06-13	criteria provided, single submitter	clinical testing
New York Genome Center	RCV002467559	SCV002764412	uncertain significance	Familial partial lipodystrophy, Dunnigan type	2021-10-19	criteria provided, single submitter	clinical testing	The heterozygous c.1751G>A p.(Arg584His) variant identified in the LMNA gene has previously been reported in the literature [PMIDs:11078466,31194872] and ClinVar [ClinVar ID:48049] as variant of unknown significance in individuals with clinical features of partial familial lipodystrophy, dilatedcardiomyopathy, and Charcot-Marie-Tooth disease. This variant has been observed in seven alleles (no homozygotes) in population databases (gnomAD v2.1.1 andv3.1.1, TOPMed Freeze 5) suggesting it is not a common benign variant in the populations represented in those databases. The predicted p.(Arg584His) variant resides in exon 11 of this 12-exon gene, which is specific to Lamin A isoform along with exon 12, whereas there is no definitive genotype-phenotype relationships for the variants residing in these exons. In silico predictions are in favor of damaging effect of the c.1751G>A variant (CADD v1.6= 28.8, REVEL= 0.730), however, no functional studies have been performed. Based on available evidence, this heterozygous c.1751G>A p.(Arg584His) variant identified in the LMNA gene is reported as Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002504919	SCV002815534	uncertain significance	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	2021-12-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162351	SCV003900569	uncertain significance	Cardiovascular phenotype	2022-11-01	criteria provided, single submitter	clinical testing	The p.R584H variant (also known as c.1751G>A), located in coding exon 11 of the LMNA gene, results from a G to A substitution at nucleotide position 1751. The arginine at codon 584 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in the heterozygous state in unrelated individuals reported to have familial partial lipodystrophy (FPLD) (Hegele RA et al. J Clin Endocrinol Metab, 2000 Sep;85:3431-5; Vigouroux C et al. Diabetes, 2000 Nov;49:1958-62; Sekizkardes H et al. J Clin Endocrinol Metab, 2019 08;104:3068-3076; Eldin AJ et al. Clin Endocrinol (Oxf), 2021 06;94:1043-1053). This variant has also been detected in the homozygous state in an individual with FPLD whose heterozygous parents were considered to be unaffected (Mory PB et al. Eur J Endocrinol, 2012 Sep;167:423-31). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000057355	SCV004124994	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing	LMNA: PP3
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057355	SCV000088468	not provided	not provided		no assertion provided	not provided