Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Blueprint Genetics | RCV000208352 | SCV000264013 | uncertain significance | Primary familial hypertrophic cardiomyopathy | 2015-03-17 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000454519 | SCV000539538 | uncertain significance | not specified | 2016-10-20 | criteria provided, single submitter | clinical testing | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 Emery-Dreifuss proband |
Genomic Research Center, |
RCV000785171 | SCV000923738 | uncertain significance | Congenital muscular dystrophy due to LMNA mutation | 2021-02-06 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000812762 | SCV000953085 | uncertain significance | Charcot-Marie-Tooth disease type 2 | 2022-11-03 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 545 of the LMNA protein (p.Arg545Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant Emery-Dreifuss muscular dystrophy (PMID: 19589617). ClinVar contains an entry for this variant (Variation ID: 66862). 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. |
Ce |
RCV000057347 | SCV001147466 | pathogenic | not provided | 2016-10-01 | criteria provided, single submitter | clinical testing | |
Broad Center for Mendelian Genomics, |
RCV001004948 | SCV001164473 | uncertain significance | Emery-Dreifuss muscular dystrophy 2, autosomal dominant | 2018-12-03 | criteria provided, single submitter | research | The heterozygous p.Arg545Cys variant in LMNA was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant was absent from large population studies. 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 vitro functional studies with myoblasts from 2 individuals with this variant in the heterozygous state and additional computation tools provide some evidence that the p.Arg545Cys variant may impact protein function by affecting gene expression, proliferation, senescence, and differentiation, but not protein stability (PMID: 19589617, 24375749). However, these types of assays may not accurately represent biological function. This variant has also been reported in ClinVar as a VUS in association with an individual with Emery-Dreifuss muscular dystrophy (Variation ID: 66862). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS3_Moderate (Richards 2015). |
Molecular Genetics Laboratory, |
RCV001174246 | SCV001337376 | uncertain significance | Charcot-Marie-Tooth disease | criteria provided, single submitter | clinical testing | ||
Personalized Diabetes Medicine Program, |
RCV001174410 | SCV001337548 | uncertain significance | Monogenic diabetes | 2018-03-27 | criteria provided, single submitter | research | ACMG criteria: PP3 (10 predictors, REVEL=0.828), PM2 (absent db), PM1 (c-terminal globular domain in PMID:12057196 and PKC Alpha Binding site on http://www.umd.be/LMNA/), possible PS3 (impaired proliferation and differentiation capacities of myoblasts in PMID:19589617 and 21535365)=VUS |
Color Diagnostics, |
RCV001185752 | SCV001352027 | uncertain significance | Cardiomyopathy | 2022-11-08 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with cysteine at codon 545 of the lamin A 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Emery-Dreifuss muscular dystrophy (PMID: 19589617). This variant has not been identified 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. |
CHEO Genetics Diagnostic Laboratory, |
RCV001185752 | SCV002041915 | uncertain significance | Cardiomyopathy | 2020-01-03 | criteria provided, single submitter | clinical testing | |
Phosphorus, |
RCV000454519 | SCV002073431 | uncertain significance | not specified | 2022-01-13 | criteria provided, single submitter | clinical testing | This missense variant results in a substitution of arginine with cysteine at codon 545 of the LMNA gene (transcript NM_170707.3). This variant has been reported in ClinVar (66862) NM_170707.4 (LMNA):c.1633C>T (p.Arg545Cys). The variant has not occurred in population databases. This position is conserved. In silico functional algorithms agree, predicting it as probably damaging (PolyPhen), deleterious (SIFT), and pathogenic (REVEL). This variant has been observed in an individual with severe autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD). Functional analysis performed on myoblasts derived from this patient demonstrated impaired proliferation and differentiation (PMID: 19589617). A different missense change at this codon (R545H) has been observed in an individual with lipodystrophy (PMID: 27919367). In conclusion, the available evidence is insufficient to determine the pathogenicity of this variant. Therefore, it is classified as a Variant of Uncertain Significance. |
All of Us Research Program, |
RCV003996506 | SCV004818705 | uncertain significance | Primary dilated cardiomyopathy | 2023-08-15 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with cysteine at codon 545 of the lamin A 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Emery-Dreifuss muscular dystrophy (PMID: 19589617). This variant has not been identified 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, |
RCV000057347 | SCV000088460 | not provided | not provided | no assertion provided | not provided |