Submissions for variant NM_170707.4(LMNA):c.1633C>T (p.Arg545Cys)

gnomAD frequency: 0.00001  dbSNP: rs267607613

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, Mass General Brigham Personalized 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, Shahid Beheshti University of Medical Sciences	RCV000785171	SCV000923738	uncertain significance	Congenital muscular dystrophy due to LMNA mutation	2021-02-06	criteria provided, single submitter	clinical testing
Invitae	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.
CeGaT Center for Human Genetics Tuebingen	RCV000057347	SCV001147466	pathogenic	not provided	2016-10-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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, London Health Sciences Centre	RCV001174246	SCV001337376	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	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, LLC DBA Color Health	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, Children's Hospital of Eastern Ontario	RCV001185752	SCV002041915	uncertain significance	Cardiomyopathy	2020-01-03	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	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, National Institutes of Health	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, Singapore	RCV000057347	SCV000088460	not provided	not provided		no assertion provided	not provided