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

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color	RCV000778039	SCV000914152	uncertain significance	Cardiomyopathy	2018-06-18	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This is a missense variant located in the rod domain of the LMNA protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/126664 non-Finnish European chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000732408	SCV000860365	uncertain significance	not provided	2018-03-23	criteria provided, single submitter	clinical testing
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	2017-11-02	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) but has not been reported in the literature in individuals with an LMNA-related disease. ClinVar contains an entry for this variant (Variation ID: 200964). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.