Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000150939 | SCV000198595 | uncertain significance | not specified | 2014-02-27 | criteria provided, single submitter | clinical testing | The Arg166Gln variant in LMNA has not been previously reported in individuals wi th cardiomyopathy. Data from large European and African American cohorts is insu fficient to assess whether this variant is present in the general population. Co mputational prediction tools and conservation analysis do not provide strong sup port for or against an impact to the protein. Additional information is needed t o fully assess the clinical significance of the Arg166Gln variant. |
Gene |
RCV000732765 | SCV000293894 | uncertain significance | not provided | 2016-03-03 | criteria provided, single submitter | clinical testing | The R166Q variant in the LMNA gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R166Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However the 1000 Genomes Project reports R166Q was observed in 4/186 alleles (2%) from a Chinese subpopulation indicating it may be a rare variant in this population. The R166Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R166Q as a variant of uncertain significance. |
Invitae | RCV000653861 | SCV000775751 | likely pathogenic | Charcot-Marie-Tooth disease type 2 | 2024-01-25 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 166 of the LMNA protein (p.Arg166Gln). This variant is present in population databases (rs267607570, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal dominant congenital muscular dystrophy (PMID: 28688748). ClinVar contains an entry for this variant (Variation ID: 163866). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg166 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18585512, 19638735, 26084686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Eurofins Ntd Llc |
RCV000732765 | SCV000860751 | uncertain significance | not provided | 2018-04-19 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000771896 | SCV000904660 | uncertain significance | Cardiomyopathy | 2023-12-11 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with glutamine at codon 166 of the lamin A/C proteins. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with congenital muscular dystrophy (PMID: 28688748). This variant has been identified in 10/208042 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. |
Genetic Services Laboratory, |
RCV000150939 | SCV002066094 | uncertain significance | not specified | 2018-02-26 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002336298 | SCV002644010 | uncertain significance | Cardiovascular phenotype | 2020-11-21 | criteria provided, single submitter | clinical testing | The p.R166Q variant (also known as c.497G>A), located in coding exon 2 of the LMNA gene, results from a G to A substitution at nucleotide position 497. The arginine at codon 166 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a single patient who presented with a congenital muscular dystrophy phenotype, but additional information regarding zygosity was unavailable (Sframeli M et al. Neuromuscul Disord, 2017 Sep;27:793-803). 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. |
Fulgent Genetics, |
RCV002505147 | SCV002816609 | uncertain significance | Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy, Dunnigan type; Mandibuloacral dysplasia with type A lipodystrophy; Congenital muscular dystrophy due to LMNA mutation; Emery-Dreifuss muscular dystrophy 3, autosomal recessive; Restrictive dermopathy 2 | 2021-11-08 | criteria provided, single submitter | clinical testing |