Submissions for variant NM_170707.4(LMNA):c.647G>A (p.Arg216His) (rs757041809)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182395	SCV000234737	uncertain significance	not specified	2016-09-12	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the LMNA gene. The R216H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R216H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. A different missense variant affecting the same residue (R216C) has been reported in HGMD in association with DCM (Stenson et al., 2014), however, the pathogenicity of this variant has not been definitively determined. R216H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae	RCV000474813	SCV000548868	uncertain significance	Charcot-Marie-Tooth disease, type 2	2019-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 216 of the LMNA protein (p.Arg216His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs757041809, ExAC no frequency). This variant has been observed in an individual affected with dilated cardiomyopathy (PMID: 30420677). ClinVar contains an entry for this variant (Variation ID: 200964). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000732408	SCV000860365	uncertain significance	not provided	2018-03-23	criteria provided, single submitter	clinical testing
Color	RCV000778039	SCV000914152	uncertain significance	Cardiomyopathy	2019-11-24	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre	RCV001172621	SCV001335684	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing