Submissions for variant NM_170707.4(LMNA):c.1196G>A (p.Arg399His)

gnomAD frequency: 0.00004  dbSNP: rs267607563

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000057256	SCV000234696	uncertain significance	not provided	2023-11-07	criteria provided, single submitter	clinical testing	In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19796712, 24623722, 24943589, 17711925, 27884173, 28663758, 27841971, 24563359, 34426522, 35772917, 10939567, 34975533, 27845687, 32041611, 17612587)
Invitae	RCV000550366	SCV000657794	uncertain significance	Charcot-Marie-Tooth disease type 2	2024-01-17	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 399 of the LMNA protein (p.Arg399His). This variant is present in population databases (rs267607563, gnomAD 0.01%). This missense change has been observed in individual(s) with familial partial lipodystrophy type 2 (PMID: 17711925). This variant is also known as c.3172G>A. ClinVar contains an entry for this variant (Variation ID: 66794). 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%. Experimental studies have shown that this missense change affects LMNA function (PMID: 17612587, 24623722). 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.
Color Diagnostics, LLC DBA Color Health	RCV001184773	SCV001350836	uncertain significance	Cardiomyopathy	2023-05-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 399 of the LMNA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant causes abnormal nuclear morphology (PMID: 17612587), disrupts interactions with a subset of its binding partners (PMID: 24623722), and alters expression of molecules involved in extracellular matrix remodeling and TGF-beta signaling. This variant has been reported in two individuals affected with lipodystrophy (PMID: 17711925, 27845687). This variant has been identified in 7/248922 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.
Ambry Genetics	RCV002336207	SCV002642014	uncertain significance	Cardiovascular phenotype	2023-06-06	criteria provided, single submitter	clinical testing	The p.R399H variant (also known as c.1196G>A), located in coding exon 7 of the LMNA gene, results from a G to A substitution at nucleotide position 1196. The arginine at codon 399 is replaced by histidine, an amino acid with highly similar properties. This alteration was reported in a subject with lipodystrophy and insulin resistant diabetes. Family studies noted the alteration was not reported in the proband's unaffected maternal cousin and brother (Decaudain A et al. J Clin Endocrinol Metab, 2007 Dec;92:4835-44). Experimental studies note a possible diruption of lamin A binding and fibroblast studies note that this alteration may alter nuclear morphology (Caron M et al. Cell Death Differ, 2007 Oct;14:1759-67; Dittmer TA et al. Mol Biol Cell, 2014 May;25:1493-510). This alteration has also been reported in a biobank cohort (Lazarte J et al. J Am Coll Cardiol, 2022 Jul;80:50-59). This amino acid position is not well 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.
Revvity Omics, Revvity	RCV000057256	SCV003814711	uncertain significance	not provided	2019-12-20	criteria provided, single submitter	clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057256	SCV000088369	not provided	not provided		no assertion provided	not provided