Submissions for variant NM_170707.4(LMNA):c.991C>T (p.Arg331Trp)

gnomAD frequency: 0.00001  dbSNP: rs879253898

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236116	SCV000292721	likely pathogenic	not provided	2023-09-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10939567, 31383942, 31476771)
Color Diagnostics, LLC DBA Color Health	RCV001176603	SCV001340631	uncertain significance	Cardiomyopathy	2023-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 331 of the lamin A/C proteins. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may impact RNA splicing by creating a new splice donor site. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with LMNA-related disorders in the literature. This variant has been identified in 3/250056 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Arg331Gln, is known to cause dilated cardiomyopathy (ClinVar variation ID: 48098), indicating that arginine at this position is important for LMNA protein function. 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.
Invitae	RCV001857795	SCV002119043	likely pathogenic	Charcot-Marie-Tooth disease type 2	2023-10-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 331 of the LMNA protein (p.Arg331Trp). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 245682). 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. This variant disrupts the p.Arg331 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19875404, 28790152). 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.
Ambry Genetics	RCV002379039	SCV002691021	uncertain significance	Cardiovascular phenotype	2020-09-17	criteria provided, single submitter	clinical testing	The p.R331W variant (also known as c.991C>T), located in coding exon 6 of the LMNA gene, results from a C to T substitution at nucleotide position 991. The arginine at codon 331 is replaced by tryptophan, an amino acid with dissimilar properties. An alteration at the same amino acid position, p.R331Q (c.992G>A), has been described as a Dutch founder mutation and segregates with LMNA-related disease in multiple families (Benedetti S et al. Neurology, 2007 Sep;69:1285-92; Møller DV et al. Eur. J. Heart Fail., 2009 Nov;11:1031-5; Hoorntje ET et al. Circ Cardiovasc Genet, 2017 Aug;10:[Epub ahead of print]; Wu L et al. Can J Neurol Sci, 2018 05;45:262-268). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
New York Genome Center	RCV003227732	SCV003925261	uncertain significance	Dilated cardiomyopathy 1A; Restrictive dermopathy 2	2022-08-10	criteria provided, single submitter	clinical testing	The c.991C>T, p.(Arg331Trp) variant identified in the LMNA gene substitutes a well conserved Arginine for Tryptophan at amino acid 331/665 (exon 6/12) in the coiled-coil 2B domain of the encoded protein [PMID: 17377071]. The c.991C>T variant is observed in 4 alleles (0.00078% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. In silico algorithms predict this variant to be Damaging to the function of the canonical transcript (REVEL; score=0.842). This variant has been reported as both Likely Pathogenic (n=1) and as a Variant of Uncertain Significance (n=2) in ClinVar (VarID:245682), and has been reported in one individual with a presumed Laminopathy but without specific clinical details [PMID:31476771] and three individuals without documented cardiac phenotypes [PMID:31383942, Supp Table S4A]. However, a different amino acid change at the same amino acid (p.(Arg331Gln); VarID:48098) has been reported as Pathogenic in ClinVar and is reported in affected individuals in the literature [PMID:28790152]. A second independent amino acid change at the p.Arg331 position (p.(Arg331Leu)) has been reported in compound heterozygous state in a female proband with severe left ventricular systolic dysfunction, supraventricular and ventricular arrhythmias [PMID: 34768595] though it is not clear if the variant identified in trans with the p.Arg331Leu variant (p.Arg216His) is causative of the phenotype, the p.Arg331Leu variant alone is causative, or both variants contribute to the phenotype. Based on available evidence this c.991C>T p.(Arg331Trp) variant identified in LMNA is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV003998898	SCV004823637	uncertain significance	Primary dilated cardiomyopathy	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 331 of the lamin A/C proteins. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may impact RNA splicing by creating a new splice donor site. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with LMNA-related disorders in the literature. This variant has been identified in 3/250056 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Arg331Gln, is known to cause dilated cardiomyopathy (ClinVar variation ID: 48098), indicating that arginine at this position is important for LMNA protein function. 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.