ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1634G>A (p.Arg545His) (rs142191737)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 likely pathogenic not provided 2017-10-17 criteria provided, single submitter clinical testing A R545H variant that is likely pathogenic has been identified in the LMNA gene. The R545H variant in the LMNA gene was previously identified in one patient in a cohort of LMNA variant carriers who had known cardiac involvement or a family history of cardiac involvement (van Rijsingen et al., 2013). This variant has also been reported in a patient with lipodystrophy (Chan et al., 2016). Additionally, this variant has been reported in several individuals at GeneDx with various levels of cardiac involvement. The R545H variant is observed in 38/75898 (0.05%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The R545H variant is a conservative amino acid substitution, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Nevertheless, this substitution occurs at a position that is conserved among mammals and is located within the C-terminal tail domain. A variant in the same residue (R545C) has been reported in association with muscular dystrophy (Kandert et al., 2009). Additionally, missense variants in nearby residues (R541C, R541H, R541G) have been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014), further supporting the functional importance of this region of the protein.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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
Invitae RCV000468904 SCV000548853 uncertain significance Charcot-Marie-Tooth disease, type 2 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 545 of the LMNA protein (p.Arg545His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs142191737, ExAC 0.03%). This variant has been reported in multiple individuals affected with LMNA-related diseases (PMID: 22918509, 23183350, 27919367, 29791652). ClinVar contains an entry for this variant (Variation ID: 163878). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). The observation of a different missense substitution at this codon (p.Arg545Cys) in an affected individual suggests that this may be a clinically significant residue (PMID: 19589617). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000621850 SCV000736172 uncertain significance Cardiovascular phenotype 2017-12-12 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000771819 SCV000904524 uncertain significance Cardiomyopathy 2020-01-27 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001100809 SCV001257349 benign Emery-Dreifuss muscular dystrophy 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,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 Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV001101056 SCV001257625 benign Familial partial lipodystrophy 2 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,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 Clinical Services Laboratory,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 Clinical Services Laboratory,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 Clinical Services Laboratory,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 Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV001101062 SCV001257631 uncertain significance Congenital muscular dystrophy, LMNA-related 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
Erich and Hanna Klessmann Institute for Cardiovascular Research and Development,Heart and Diabetes Center North Rhine-Westphalia RCV000491650 SCV000298120 likely pathogenic Dilated cardiomyopathy 1S 2016-05-01 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV001248958 SCV001422752 uncertain significance Lipodystrophy (disease) 2020-01-22 no assertion criteria provided 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).

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