ClinVar Miner

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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