ClinVar Miner

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

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Total submissions: 10
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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

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