ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1072G>A (p.Glu358Lys)

dbSNP: rs60458016
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000057227 SCV000331050 pathogenic not provided 2016-10-04 criteria provided, single submitter clinical testing
Invitae RCV000470514 SCV000548856 pathogenic Charcot-Marie-Tooth disease type 2 2023-09-03 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 358 of the LMNA protein (p.Glu358Lys). This missense change has been observed in individual(s) with autosomal dominant LMNA-related conditions (PMID: 10939567, 20980393, 21520333, 21632249, 23183350, 24508248). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LMNA function (PMID: 11792809, 23427149). 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. ClinVar contains an entry for this variant (Variation ID: 14525).
Genetic Services Laboratory, University of Chicago RCV000502108 SCV000595623 pathogenic Muscular dystrophy 2013-02-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001420791 SCV001623153 pathogenic Emery-Dreifuss muscular dystrophy 2021-05-12 criteria provided, single submitter clinical testing Variant summary: LMNA c.1072G>A (p.Glu358Lys) results in a conservative amino acid change located in the rod domain (IPR039008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251348 control chromosomes (gnomAD). c.1072G>A has been reported in the literature (usually as a de novo variant) in several individuals affected with typical- and atypical forms of Autosomal Dominant Emery-Dreifuss Muscular Dystrophy, with- or without cardiac involvement (see e.g. Mercuri_2004, Quijano-Roy_2008, van Rijsingen_2013, Pasqualin_2014, Fan_2021); in general most of the patients had muscle involvement, but the onset, severity, distribution of muscle weakness, and presence of associated features were highly variable. These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function and demonstrated abnormal intranuclear localization of the variant protein, which was associated with defective nuclear stability (Ostlund_2001, Zwerger_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 , and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV000057227 SCV001711959 pathogenic not provided 2021-05-23 criteria provided, single submitter clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000015622 SCV001976953 pathogenic Benign scapuloperoneal muscular dystrophy with cardiomyopathy 2021-10-01 criteria provided, single submitter clinical testing PM1, PM2, PP2, PP3, PP5
Revvity Omics, Revvity Omics RCV000057227 SCV002017164 pathogenic not provided 2021-11-19 criteria provided, single submitter clinical testing
OMIM RCV000015622 SCV000035887 pathogenic Benign scapuloperoneal muscular dystrophy with cardiomyopathy 2008-08-01 no assertion criteria provided literature only
OMIM RCV000015623 SCV000035888 pathogenic Congenital muscular dystrophy due to LMNA mutation 2008-08-01 no assertion criteria provided literature only
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057227 SCV000088340 not provided not provided no assertion provided not provided

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