Submissions for variant NM_170707.4(LMNA):c.1567G>A (p.Gly523Arg)

gnomAD frequency: 0.00006  dbSNP: rs201583907

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000057323	SCV000065017	uncertain significance	not provided	2021-08-05	criteria provided, single submitter	clinical testing	The p.Gly523Arg variant in LMNA has been reported in 5 individual with dilated cardiomyopathy (DCM; Millat 2009 PMID: 19318026, Fichna 2018 PMID: 29970176, LMM data), 1 individual with limb-girdle muscular dystrophy (Magri 2015 PMID: 26404900), 1 individual with LVNC, conduction system disease and muscle weakness (LMM data), and in 2 siblings presenting with features of COL6A2 related myopathy as well as Emery-Dreifuss muscular dystrophy (Chapon 2008, conference abstract only). In the family described by Chapon et al, the myopathy present in both sibs was believed to be due recessively inherited COL6A2 variants. The LMNA variant was present in one of the sibs as well as the father, who was clinically normal but showed dystrophic changes as well as mild deficit of collagen 6 fibers. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 48045 ) and has been identified in 0.01% (8/68028) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3.
GeneDx	RCV000057323	SCV000234703	uncertain significance	not provided	2021-07-08	criteria provided, single submitter	clinical testing	Observed in individuals with dilated cardiomyopathy (DCM), limb girdle muscular dystrophy (LGMD), and/or familial partial lipodystrophy, Dunnigan variety (FPLD2); however, familial segregation studies were not described (Millat et al., 2009; Millat et al., 2011; Pugh et al., 2014; Haas et al., 2015; Magri et al., 2015, Fichna et al., 2018, Park et al., 2020, Vasandani et al., 2020); Observed to segregate with DCM, conduction disease, and/or subtle right ventricular abnormalities in individuals from one family, but was also observed in unaffected individuals in this family (Hylind et al., 2019); Published functional studies demonstrate altered ability of LMNA protein to interact with 5% of its protein targets (Dittmer et al., 2014); nevertheless, it is unclear how these studies may translate to a pathogenic role in vivo; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID #48045; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 10939567, 20074070, 27535533, 24623722, 32193531, 31383942, 30919684, 31744510, 29970176, 26633542, 27576561, 28679633, 28663758, 19318026, 25163546, 26404900, 21846512, 24846508, 24503780, 24375749)
Ambry Genetics	RCV000245950	SCV000320458	uncertain significance	Cardiovascular phenotype	2023-07-20	criteria provided, single submitter	clinical testing	The p.G523R variant (also known as c.1567G>A), located in coding exon 9 of the LMNA gene, results from a G to A substitution at nucleotide position 1567. The glycine at codon 523 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in individuals with dilated cardiomyopathy (DCM) (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Millat G et al. Clin. Biochem., 2009 Jun;42:892-8; Millat G et al. Eur J Med Genet Aug;54:e570-5; Hylind RJ et al. Circ Genom Precis Med. 2019 Mar;12(3):e002463). This variant has also been detected in individuals with limb girdle muscular dystrophy (LGMD); however, in some cases, other variants in myopathy-related genes were also detected (Magri F et al. BMC Neurol, 2015 Sep;15:172; Fichna JP et al. Hum. Genomics, 2018 07;12:34). This variant has also been detected in two individual from familial partial lipodystrophy cohort; however details were limited (Vasandani C et al. J Endocr Soc. 2022 Oct;6(12):bvac155). This variant was also reported in 35 individuals from an electronic medical record review exome cohort, including one DCM case and two individuals with chronic kidney disease (Park J et al. Genet Med, 2020 01;22:102-111). 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.
Eurofins Ntd Llc (ga)	RCV000057323	SCV000336479	uncertain significance	not provided	2018-08-16	criteria provided, single submitter	clinical testing
Invitae	RCV000474372	SCV000548848	uncertain significance	Charcot-Marie-Tooth disease type 2	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 523 of the LMNA protein (p.Gly523Arg). This variant is present in population databases (rs201583907, gnomAD 0.01%). This missense change has been observed in individual(s) with limb girdle muscular dystrophy, dilated cardiomyopathy, or dyslipidemias (PMID: 19318026, 24503780, 26404900, 29970176, 32041611). ClinVar contains an entry for this variant (Variation ID: 48045). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 24623722). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001181346	SCV001346472	uncertain significance	Cardiomyopathy	2023-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 523 of the LMNA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental study using a yeast two hybrid system has shown that this variant may lead to ~5% lost protein interactions (PMID: 24623722), but functional and clinical significance of this observation is not known. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 19318026, 21846512, 24503780, 29961767, 30919684, 31383942), in an individual affected with hypertrophic cardiomyopathy (PMID: 35026164), and in individuals affected with limb girdle muscular dystrophy (PMID: 26404900, 34720847). This variant has been reported in four members of one family (PMID: 30919684); one carrier was affected with subtle right ventricular abnormalities, and the carrier's parent was affected with dilated cardiomyopathy and conduction disease. This variant has also been reported in individuals affected with laminopathy (PMID: 28663758, 31744510, 32193531, 32826072), in individuals affected with chronic kidney disease (PMID: 31383942), and in multiple apparently healthy individuals in a large biobank (PMID: 31383942). This variant has been identified in 22/264998 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Johns Hopkins Genomics, Johns Hopkins University	RCV001250579	SCV001425445	uncertain significance	Dilated cardiomyopathy 1A	2020-02-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001330499	SCV001522189	uncertain significance	Lethal tight skin contracture syndrome	2019-06-21	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000057323	SCV003816997	uncertain significance	not provided	2022-10-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041324	SCV003845078	uncertain significance	not specified	2023-02-20	criteria provided, single submitter	clinical testing	Variant summary: LMNA c.1567G>A (p.Gly523Arg) results in a non-conservative amino acid change located in the Lamin tail domain (IPR001322) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.6e-05 in 233624 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LMNA causing Cardiomyopathy (8.6e-05 vs 0.00025), allowing no conclusion about variant significance. c.1567G>A has been reported in the literature in individuals affected with limb girdle muscular dystrophy, dilated cardiomyopathy, or other dyslipidemias (Millat_2011, Pugh_2014, Park_2020, etc). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Dittmer_2014). Nine ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=8) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001181346	SCV004240717	uncertain significance	Cardiomyopathy	2022-07-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996456	SCV004817446	uncertain significance	Primary dilated cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 523 of the LMNA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental study using a yeast two hybrid system has shown that this variant may lead to ~5% lost protein interactions (PMID: 24623722), but functional and clinical significance of this observation is not known. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 19318026, 21846512, 24503780, 29961767, 30919684, 31383942), in an individual affected with hypertrophic cardiomyopathy (PMID: 35026164), and in individuals affected with limb girdle muscular dystrophy (PMID: 26404900, 34720847). This variant has been reported in four members of one family (PMID: 30919684); one carrier was affected with subtle right ventricular abnormalities, and the carrier's parent was affected with dilated cardiomyopathy and conduction disease. This variant has also been reported in individuals affected with laminopathy (PMID: 28663758, 31744510, 32193531, 32826072), in individuals affected with chronic kidney disease (PMID: 31383942), and in multiple apparently healthy individuals in a large biobank (PMID: 31383942). This variant has been identified in 22/264998 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057323	SCV000088436	not provided	not provided		no assertion provided	not provided
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678714	SCV000804881	likely pathogenic	Left ventricular noncompaction	2017-04-19	flagged submission	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000057323	SCV001743354	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000057323	SCV001807449	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000057323	SCV001918068	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000057323	SCV001931676	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000057323	SCV001954184	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000057323	SCV001963796	uncertain significance	not provided		no assertion criteria provided	clinical testing