Submissions for variant NM_170707.4(LMNA):c.357C>T (p.Arg119=) (rs41313880)

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000041345	SCV000604108	likely benign	not specified	2017-03-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000249770	SCV000318670	benign	Cardiovascular phenotype	2013-04-11	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Athena Diagnostics Inc	RCV000041345	SCV000614029	benign	not specified	2017-04-14	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000768710	SCV000900080	benign	Cardiomyopathy	2017-02-10	criteria provided, single submitter	clinical testing
CSER_CC_NCGL; University of Washington Medical Center	RCV000148598	SCV000190313	likely benign	Emery-Dreifuss muscular dystrophy	2014-06-01	no assertion criteria provided	research
CSER_CC_NCGL; University of Washington Medical Center	RCV000211467	SCV000212169	likely benign	Primary dilated cardiomyopathy	2015-03-11	criteria provided, single submitter	research
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000057395	SCV000780300	uncertain significance	not provided	2018-02-28	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	RCV000057395	SCV000280919	likely benign	not provided	2015-12-21	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Color	RCV000768710	SCV000902999	benign	Cardiomyopathy	2018-03-08	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000041345	SCV000113216	likely benign	not specified	2015-08-27	criteria provided, single submitter	clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057395	SCV000088508	not provided	not provided		no assertion provided	not provided
Genetic Services Laboratory, University of Chicago	RCV000041345	SCV000595596	benign	not specified	2013-02-08	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000148598	SCV000348781	likely benign	Emery-Dreifuss muscular dystrophy	2016-06-14	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000041345	SCV000917597	benign	not specified	2018-07-30	criteria provided, single submitter	clinical testing	Variant summary: LMNA c.357C>T (p.Arg119Arg) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0033 in 277140 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 13-fold of the estimated maximal expected allele frequency for a pathogenic variant in LMNA causing Cardiomyopathy phenotype (0.00025), strongly suggesting that the variant is benign. The variant, c.357C>T, has been reported in the literature and classified as likely benign by the authors (Dorschner_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (6x likely benign/benign, 1x VUS). Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV000228540	SCV000291559	benign	Charcot-Marie-Tooth disease, type 2	2018-01-17	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000041345	SCV000065038	benign	not specified	2012-06-06	criteria provided, single submitter	clinical testing	Arg119Arg in exon 2 of LMNA: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and has been identified in 0.3% (24/7020) of European American chromosomes from a broad population by th e NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs413 13880).
PreventionGenetics	RCV000041345	SCV000316409	likely benign	not specified		criteria provided, single submitter	clinical testing