Submissions for variant NM_170707.4(LMNA):c.1633C>T (p.Arg545Cys) (rs267607613)

Total submissions: 10

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,Partners HealthCare 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	likely pathogenic	Congenital muscular dystrophy, LMNA-related	2019-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV000812762	SCV000953085	uncertain significance	Charcot-Marie-Tooth disease, type 2	2018-10-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 545 of the LMNA protein (p.Arg545Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Emery-Dreifuss muscular dystrophy (PMID: 19589617). ClinVar contains an entry for this variant (Variation ID: 66862). Experimental studies utilizing patient-derived cells have shown that this missense change leads to abnormal nuclear morphology and impairs LMNA protein function (PMID: 19589617, 17761684, 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 Praxis fuer Humangenetik Tuebingen	RCV000057347	SCV001147466	likely pathogenic	not provided	2019-02-01	criteria provided, single submitter	clinical testing
Broad Institute Rare Disease Group,Broad Institute	RCV001004948	SCV001164473	uncertain significance	Limb-girdle muscular dystrophy, type 1B	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	RCV001185752	SCV001352027	uncertain significance	Cardiomyopathy	2019-09-15	criteria provided, single submitter	clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057347	SCV000088460	not provided	not provided		no assertion provided	not provided