Submissions for variant NM_170707.4(LMNA):c.1657G>A (p.Asp553Asn) (rs373671419)

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Total submissions: 6

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000334194	SCV000339617	uncertain significance	not provided	2016-02-12	criteria provided, single submitter	clinical testing
Invitae	RCV000541582	SCV000657805	uncertain significance	Charcot-Marie-Tooth disease, type 2	2019-05-31	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 553 of the LMNA protein (p.Asp553Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs373671419, ExAC no frequency). This variant has been reported in an individual affected with LMNA-related disease (PMID: 27884249). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15". The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute	RCV000622473	SCV000740349	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2016-11-29	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000825772	SCV000967237	likely benign	not specified	2019-03-10	criteria provided, single submitter	clinical testing	The p.Asp553Asn variant in LMNA is classified as likely benign because it has been identified in 0.06% (15/24926) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Additionally, 2 mammals (rat and mouse) have an asparagine (Asn) at this position despite relatively nearby amino acid conservation. In addition, most computational tools do not suggest a high likelihood of impact to the protein. ACMG/AMP Criteria applied: BS1_supporting, BP4.
Molecular Genetics Laboratory,London Health Sciences Centre	RCV001172624	SCV001335687	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Color	RCV001183038	SCV001348688	likely benign	Cardiomyopathy	2019-10-18	criteria provided, single submitter	clinical testing

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