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

gnomAD frequency: 0.00002  dbSNP: rs757041809

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000732408	SCV000234737	uncertain significance	not provided	2022-03-08	criteria provided, single submitter	clinical testing	Reported in at least one patient with DCM with abnormal nuclei in approximately 15% of cultured fibroblasts (Van Tienen et al., 2019; Verdonschot et al., 2020); also reported in one patient with Charcot-Marie-Tooth (Volodarsky et al., 2021); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32880476, 30420677, 32376792)
Invitae	RCV000474813	SCV000548868	likely pathogenic	Charcot-Marie-Tooth disease type 2	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 216 of the LMNA protein (p.Arg216His). This variant is present in population databases (rs757041809, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of autosomal dominant LMNA-related conditions (PMID: 30420677, 32376792, 32880476, 34495297). ClinVar contains an entry for this variant (Variation ID: 200964). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg216 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23183350, 27506821, 28878402, 29237675, 29943882, 30007954). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Eurofins Ntd Llc (ga)	RCV000732408	SCV000860365	uncertain significance	not provided	2018-03-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000778039	SCV000914152	uncertain significance	Cardiomyopathy	2022-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 216 of the lamin A/C protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 34768595). A different variant occurring at the same codon, p.Arg216Cys, is a well documented pathogenic mutation (Clinvar variation ID: 200938), indicating that arginine at this position is important for LMNA protein function. This variant has been identified in 7/282556 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001172621	SCV001335684	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354479	SCV002654768	uncertain significance	Cardiovascular phenotype	2022-07-26	criteria provided, single submitter	clinical testing	The p.R216H variant (also known as c.647G>A), located in coding exon 4 of the LMNA gene, results from a G to A substitution at nucleotide position 647. The arginine at codon 216 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in dilated cardiomyopathy (DCM) cohorts, as well as a Charcot-Marie-Tooth cohort; however, clinical details were limited in these cases (Horvat C et al. Genet Med, 2019 01;21:133-143; van Tienen FHJ et al. Eur J Hum Genet, 2019 03;27:389-399; Ferradini V et al. J Clin Med, 2021 Oct;10:[ePub ahead of print]; Volodarsky M et al. J Med Genet, 2021 04;58:284-288). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002478615	SCV002778809	uncertain significance	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy, Dunnigan type; Mandibuloacral dysplasia with type A lipodystrophy; Congenital muscular dystrophy due to LMNA mutation; Emery-Dreifuss muscular dystrophy 3, autosomal recessive; Restrictive dermopathy 2	2021-11-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000732408	SCV003814720	uncertain significance	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University	RCV001775091	SCV001593106	likely pathogenic	Dilated cardiomyopathy 1A	2021-04-27	no assertion criteria provided	clinical testing