Submissions for variant NM_170707.4(LMNA):c.1634G>A (p.Arg545His)

gnomAD frequency: 0.00025  dbSNP: rs142191737

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150955	SCV000198618	uncertain significance	not specified	2018-06-12	criteria provided, single submitter	clinical testing	The p.Arg545His variant in LMNA has been reported in at least 2 individuals with sudden death, 1 individual with partial lipodystrophy, 1 individual with lipody strophy and myopathy, 4 individuals with laminopathy-associated features, and se gregated with disease in 1 affected relative (LMM data, Houben 2013, van Rijsing en 2013, Chan 2016, Campuzano 2017, Neubauer 2017, Guillin-Amarelle 2018, Olaopa 2018). This variant has been reported in ClinVar (Variation ID: 163878) and has been identified in 0.05% (38/75898) of European chromosomes by the Genome Aggre gation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs142191737). 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. In vitro functional studies provide some evidence that t he p.Arg545His variant may reduce sodium current (Olaopa 2018). However, these types of assays may not accurately represent biological function.Computational p rediction tools and conservation analysis do not provide strong support for or a gainst an impact to the protein. In summary, due to conflicting evidence and var iable phenotypes of affected individuals carrying the variant, the clinical sign ificance of the p.Arg545His variant is uncertain.ACMG/AMP criteria applied: PS3_ Moderate, PS4_Moderate.
GeneDx	RCV000505801	SCV000234709	uncertain significance	not provided	2024-07-24	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in individuals with dilated cardiomyopathy, unspecified arrhythmia, cathecholaminergic polymorphic ventricular tachycardia, isolated atrial fibrillation, left ventricle non-compaction, or metabolic syndrome and lipodystrophy, with or without cardiomyopathy and proximal myopathy, but full familial segregation information was generally not provided (PMID: 29791652, 29253866, 30847666, 30420677, 27919367, 33803191, 35449878, 36788754); Reported in the apparent homozygous state in two siblings with lipodystrophy with near-generalized loss of subcutaneous fat, diabetes mellitus, extreme hypertriglyceridemia, hepatic steatosis, as well as intellectual disability, short stature, joint contractures, and cataracts; two heterozygous relatives were overweight and had acanthosis nigricans, but no evidence of lipodystrophy (PMID: 31857427); Identified, both independently and/or in conjunction with additional variants, in other unrelated individuals referred for genetic testing at GeneDx, including one individual with a de novo pathogenic variant in another gene that was sufficient to explain their phenotype.; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27498076, 30564623, 28663758, 26332594, 23183350, 29557732, 28255936, 27919367, 28074886, 29253866, 30847666, 31383942, 30420677, 34426522, 33803191, 32041611, 37652022, 34806324, 35205065, 33713793, 35449878, 35846372, 35772917, 36788754, 10939567, 29791652, 31857427)
Eurofins Ntd Llc (ga)	RCV000505801	SCV000338870	uncertain significance	not provided	2017-01-03	criteria provided, single submitter	clinical testing
Claritas Genomics	RCV000449630	SCV000537830	uncertain significance	Peripheral neuropathy	2016-08-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468904	SCV000548853	likely benign	Charcot-Marie-Tooth disease type 2	2024-01-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621850	SCV000736172	uncertain significance	Cardiovascular phenotype	2023-11-29	criteria provided, single submitter	clinical testing	The p.R545H variant (also known as c.1634G>A), located in coding exon 10 of the LMNA gene, results from a G to A substitution at nucleotide position 1634. The arginine at codon 545 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported as heterozygous and homozygous in association with different types of LMNA-related disease (van Rijsingen IA et al. Eur. J. Heart Fail., 2013 Apr;15:376-84; Chan D et al. J Clin Lipidol. 2016 Sep;10:1488-1491; Neubauer J et al. Eur. J. Hum. Genet., 2017 04;25:404-409; Guillín-Amarelle C et al. Arch Endocrinol Metab, 2018 Jun;62:376-382; Patni N et al. J Med Genet, 2020 06;57:422-426). This variant has also been detected in 125 participants from a biobank cohort; however, details were limited (Lazarte J et al. J Am Coll Cardiol. 2022 Jul;80(1):50-59). 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.
Color Diagnostics, LLC DBA Color Health	RCV000771819	SCV000904524	uncertain significance	Cardiomyopathy	2023-11-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 545 of the LMNA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In a functional study, homozygous LMNA-R545H knock-in mice were reported to have reduced sodium current and increased sinus arrhythmias (Wu et al, 2020). A separate study correlated the presence of cytoplasmically located PML nuclear bodies with cells from patients with laminopathies (PMID: 22918509). However, clinical relevance of this observation is unknown. This variant has been observed in individuals affected with possible LMNA-related diseases (PMID: 22918509, 23183350, 27529282, 27919367, 29557732, 29791652, 30420677, 31857427, 33803191, 35449878; Wu et al, 2020). This variant has been identified in 48/193996 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.
Illumina Laboratory Services, Illumina	RCV001100810	SCV001257350	uncertain significance	Lipoatrophy with Diabetes, Hepatic Steatosis, Hypertrophic Cardiomyopathy, and Leukomelanodermic Papules	2018-10-11	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001101055	SCV001257624	uncertain significance	Emery-Dreifuss muscular dystrophy 2, autosomal dominant	2018-10-11	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001101057	SCV001257626	uncertain significance	Lethal tight skin contracture syndrome	2018-10-11	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001101058	SCV001257627	uncertain significance	Dilated cardiomyopathy 1A	2018-10-11	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001101059	SCV001257628	uncertain significance	Mandibuloacral dysplasia with type A lipodystrophy	2018-10-11	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001101060	SCV001257629	uncertain significance	Charcot-Marie-Tooth disease type 2B1	2018-10-11	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001101061	SCV001257630	uncertain significance	Hutchinson-Gilford syndrome	2018-10-11	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001101062	SCV001257631	uncertain significance	Congenital muscular dystrophy due to LMNA mutation	2018-10-11	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771819	SCV001333645	uncertain significance	Cardiomyopathy	2018-09-04	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248958	SCV001422752	uncertain significance	Lipodystrophy	2020-01-22	criteria provided, single submitter	curation	The p.Arg545His variant in LMNA has been reported in 1 individual with lipodystrophy (PMID: 28074886), but has been identified in 0.05% (41/79748) of European (non-Finnish) chromosomes and other populations at lesser frequencies by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142191737). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 163878). In vitro functional studies provide some evidence that the p.Arg545His variant may slightly impact protein function (PMID: 22918509). 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. Multiple variants in the same region as p.Arg545His have been reported in association with disease in the literature and the variant is located in a region of LMNA that is thought to be essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 28663758). In summary, the clinical significance of the p.Arg545His variant is uncertain. ACMG/AMP Criteria applied: PP3, PS3_supporting, PM1_supporting, BA1 (Richards 2015).
Institute of Human Genetics, University of Leipzig Medical Center	RCV001101058	SCV001440672	uncertain significance	Dilated cardiomyopathy 1A	2019-01-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001781492	SCV002026359	pathogenic	Short stature; Microtia; Microretrognathia; 2-3 finger cutaneous syndactyly; Hypercholesterolemia; Decreased body weight; Round ear	2021-11-02	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS3, PS4, PM5_STR, PP3
Mendelics	RCV001101058	SCV002517569	uncertain significance	Dilated cardiomyopathy 1A	2022-07-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000505801	SCV002541099	uncertain significance	not provided	2022-02-11	criteria provided, single submitter	clinical testing	PP3
Revvity Omics, Revvity	RCV000505801	SCV003816991	uncertain significance	not provided	2021-05-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000505801	SCV003916514	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	LMNA: PS3:Moderate
Molecular Genetics, Royal Melbourne Hospital	RCV003993830	SCV004812651	uncertain significance	Autosomal semi-dominant severe lipodystrophic laminopathy	2023-08-01	criteria provided, single submitter	clinical testing	This sequence change in LMNA is predicted to replace arginine with histidine at codon 545, p.(Arg545His). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the lamin tail domain. There is a small physicochemical difference between arginine and histidine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.05% (41/79,748 alleles) in the European (non-Finnish) population. This variant has been reported in individuals with LMNA-related disorders, including cardiomyopathy and lipodystrophy but has also been identified in unaffected individuals (PMID: 30420677, 31857427, 33803191, 35772917). The variant has been identified as homozygous in two siblings with lipodystrophy (PMID: 31857427). A homozygous knock-in mouse model of the variant demonstrated reduced voltage-gated sodium current, prolonged PR and QTc intervals, and increased sinus arrhythmias, which were absent in the heterozygous knock-in model (Wu et al. https://doi.org/10.1161/circ.142.suppl_3.12627Circulation). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.769). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3, PS3_Supporting.
All of Us Research Program, National Institutes of Health	RCV003998208	SCV004818816	uncertain significance	Primary dilated cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 545 of the LMNA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In a functional study, homozygous LMNA-R545H knock-in mice were reported to have reduced sodium current and increased sinus arrhythmias (Wu et al, 2020). A separate study correlated the presence of cytoplasmically located PML nuclear bodies with cells from patients with laminopathies (PMID: 22918509). However, clinical relevance of this observation is unknown. This variant has been observed in individuals affected with possible LMNA-related diseases (PMID: 22918509, 23183350, 27529282, 27919367, 29557732, 29791652, 30420677, 31857427, 33803191, 35449878; Wu et al, 2020). This variant has been identified in 48/193996 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.
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen	RCV000491650	SCV000298120	likely pathogenic	Dilated cardiomyopathy 1S	2016-05-01	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000505801	SCV001924031	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000505801	SCV001932887	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000505801	SCV001954995	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000505801	SCV001973367	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532675	SCV004755390	uncertain significance	LMNA-related disorder	2024-01-10	no assertion criteria provided	clinical testing	The LMNA c.1634G>A variant is predicted to result in the amino acid substitution p.Arg545His. This variant has been reported in individuals who had cardiac disease (Table S1, van Rijsingen et al. 2013. PubMed ID: 23183350; Table S4, Neubauer et al. 2017. PubMed ID: 28074886; Table S5, Klauke et al. 2017. PubMed ID: 29253866; Guillín-Amarelle et al. 2018. PubMed ID: 29791652). This variant has also been reported in individuals with lipodystrophy or dyslipidemias (Chan et al. 2016. PubMed ID: 27919367; Table S4, Dron et al. 2020. PubMed ID: 32041611). This variant is reported in 0.051% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to pathogenic (http://www.ncbi.nlm.nih.gov/clinvar/variation/163878). Different substitutions that affect the same amino acid (p.Arg545Cys and p.Arg545Ser) have also been documented in association with Emery-Dreifuss muscular dystrophy and dilated cardiomyopathy (Kandert et al. 2009. PubMed ID: 19589617; Zhang et al. 2020. PubMed ID: 32041989). At this time, the clinical significance of the c.1634G>A (p.Arg545His) variant is uncertain due to the absence of conclusive functional and genetic evidence.