Total submissions: 21
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular 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. |
Gene |
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, |
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 | 2020-02-10 | 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, and is located in the carboxy-terminal domain. This alteration has been reported 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). Another alteration affecting the same amino acid, p.R545C (c.1633C>T), has been reported in association with Emery-Dreifuss muscular dystrophy (Kandert S et al. Eur. J. Cell Biol., 2009 Oct;88:593-608). 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 Health, |
RCV000771819 | SCV000904524 | uncertain significance | Cardiomyopathy | 2020-01-27 | criteria provided, single submitter | clinical testing | |
Illumina Clinical Services Laboratory, |
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, |
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, |
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, |
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, |
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, |
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, |
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, |
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, |
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, |
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, |
RCV000771819 | SCV001333645 | uncertain significance | Cardiomyopathy | 2018-09-04 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
RCV001101058 | SCV001440672 | uncertain significance | Dilated cardiomyopathy 1A | 2019-01-01 | criteria provided, single submitter | clinical testing | |
Erich and Hanna Klessmann Institute for Cardiovascular Research and Development, |
RCV000491650 | SCV000298120 | likely pathogenic | Dilated cardiomyopathy 1S | 2016-05-01 | no assertion criteria provided | clinical testing | |
Broad Institute Rare Disease Group, |
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). |