Submissions for variant NM_170707.4(LMNA):c.1851C>T (p.Ala617=) (rs143189394)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000041336	SCV000065029	benign	not specified	2012-02-09	criteria provided, single submitter	clinical testing	Ala617Ala in exon 11 of LMNA: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence and has been identified in 0.4% (16/3738) African American chromosomes by the NHLBI Exome Sequencing Project in a broad population (http://evs.gs.washington.edu/EVS; dbSNP rs143189394).
Invitae	RCV000234314	SCV000291555	benign	Charcot-Marie-Tooth disease, type 2	2019-12-31	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000041336	SCV000338848	benign	not specified	2016-07-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000041336	SCV000513501	benign	not specified	2015-04-16	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genetic Services Laboratory,University of Chicago	RCV000041336	SCV000595614	uncertain significance	not specified	2013-02-08	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000769733	SCV000901155	benign	Cardiomyopathy	2015-10-09	criteria provided, single submitter	clinical testing
Color	RCV000769733	SCV000913460	benign	Cardiomyopathy	2018-03-23	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000041336	SCV000917593	benign	not specified	2018-05-29	criteria provided, single submitter	clinical testing	Variant summary: LMNA c.1851C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant is found at a frequency of 0.000448 in the gnomAD database, but was observed predominantly in the African subpopulation at a frequency of 0.005139. The observed variant frequency within African control individuals in the gnomAD database is more than 20 fold above the estimated maximal expected allele frequency for a pathogenic variant in LMNA causing Cardiomyopathy phenotype (0.005139 vs. 0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.1851C>T has been reported in the literature, however this report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Molecular Genetics Laboratory,London Health Sciences Centre	RCV001173409	SCV001336497	likely benign	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing