Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000154750 | SCV000204430 | likely benign | not specified | 2014-02-17 | criteria provided, single submitter | clinical testing | Asn459Ser in exon 7 of LMNA: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , multiple mammals (cat, dog, walrus, seal, fox, and two bat species) have a ser ine (Ser) at this position despite high nearby amino acid conservation. It has a lso been identified in 1/4378 African American chromosomes by the NHLBI Exome S equencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs372011095). Additi onal computational analyses (AlignGVGD, PolyPhen2, SIFT) do not suggest a high l ikelihood of impact to the protein. Asn459Ser in exon 7 of LMNA (rs372011095; a llele frequency = 1/4378) ** |
Gene |
RCV000726125 | SCV000293361 | uncertain significance | not provided | 2018-03-13 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the LMNA gene. The N459S variant has been reported by Rodriguez et al. (2008) in a cohort of patients with cardiomyopathy, dysrhythmias, or cardiac progeria; however, phenotypic characteristics of the patient with the N459S variant was not defined. The N459S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The N459S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, the N459S variant is located in the globular carboxy-terminal tail region of the LMNA gene. |
Eurofins Ntd Llc |
RCV000726125 | SCV000342151 | uncertain significance | not provided | 2016-05-13 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000726125 | SCV000885654 | uncertain significance | not provided | 2017-06-02 | criteria provided, single submitter | clinical testing | The p.Asn459Ser variant (rs372011095) has been previously observed in a cohort of cardiomyopathy, dysrhythmias, or cardiac progeria patients (Rodriguez 2008), although no other specific clinical information is provided in relation to this patient population. This variant is also listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.003% (identified in 6 out of 210,462 chromosomes). The asparagine at codon 459 is moderately conserved considering 11 species (Alamut software v2.9), and computational analyses return mixed results regarding the effect of this variant on LMNA protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: disease causing). However, variants in nearby amino acids have been associated with Emery-Dreifuss muscular dystrophy (selected reference: Helbling-Leclerc 2002). This variant is also listed in the ClinVar database with conflicting interpretations of pathogenicity (Variation ID: 178062). Thus, based on the available information, the clinical significance of the p.Asn459Ser variant cannot be determined with certainty. |
Invitae | RCV000824275 | SCV000965168 | likely benign | Charcot-Marie-Tooth disease type 2 | 2023-12-03 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV001179779 | SCV001344552 | uncertain significance | Cardiomyopathy | 2023-11-06 | criteria provided, single submitter | clinical testing | This missense variant replaces asparagine with serine at codon 459 of the lamin A/C proteins. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 7/216196 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. |
Ambry Genetics | RCV002381491 | SCV002696405 | uncertain significance | Cardiovascular phenotype | 2023-06-23 | criteria provided, single submitter | clinical testing | The p.N459S variant (also known as c.1376A>G), located in coding exon 7 of the LMNA gene, results from an A to G substitution at nucleotide position 1376. The asparagine at codon 459 is replaced by serine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Revvity Omics, |
RCV000726125 | SCV003814709 | uncertain significance | not provided | 2019-12-24 | criteria provided, single submitter | clinical testing |