ClinVar Genomic variation as it relates to human health

The LMNA c.1745G>A variant is predicted to result in the amino acid substitution p.Arg582His. This variant has been reported in the heterozygous and homozygous states in multiple individuals with familial partial lipodystrophy (see for example, Garg et al. 2001. PubMed ID: 11231979; Akinci et al. 2017. PubMed ID: 28641778; Soyaltin et al. 2020. PubMed ID: 32685188). Different substitutions impacting the same amino acid (p.Arg582Cys, p.Arg582Ser) have also been reported in patients with partial lipodystrophy (Mory et al. 2012. PubMed ID: 22700598; Ji et al. 2013. PubMed ID: 23783098) This variant is reported in 0.0042% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-156108325-G-A). This variant is interpreted as pathogenic.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 582 of the LMNA protein (p.Arg582His). This variant is present in population databases (rs57830985, gnomAD 0.004%). This missense change has been observed in individuals with familial partial lipodystrophy (FPLD) (PMID: 10739751, 11231979, 20130076, 28641778). ClinVar contains an entry for this variant (Variation ID: 14494). 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.Arg582 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 22700598, 23783098), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

This missense variant replaces arginine with histidine at codon 582 of the lamin A 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). This variant represents a single nucleotide substitution in the 3' untranslated region of the lamin C transcript (ENST00000361308: :c.*770G>A). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. However, this variant has been reported in over 10 individuals affected with familial partial lipodystrophy, which is a rare condition characterized by an abnormal distribution of fatty tissue in the body and associated with metabolic involvement, such as diabetes, hyperlipidemia, and hepatosteatosis (PMID: 10739751, 11231979, 20130076, 28641778, 30418556, 30595509, 32193531, 32685188). This variant has been identified in 3/273962 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, the available evidence indicates that this variant is associated with familial partial lipodystrophy. However, the role of this variant in cardiomyopathy is not clear due to the lack of clinical evidence. Therefore, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy.

This missense variant replaces arginine with histidine at codon 582 of the lamin A 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). This variant represents a single nucleotide substitution in the 3' untranslated region of the lamin C transcript (ENST00000361308: :c.*770G>A). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. However, this variant has been reported in over 10 individuals affected with familial partial lipodystrophy (PMID: 10739751, 11231979, 20130076, 28641778, 30418556, 30595509, 32193531, 32685188). This variant has been identified in 3/273962 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in multiple individuals affected with familial partial lipodystrophy, but the available evidence is insufficient to determine the role of this variant in autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy.

The p.R582H variant (also known as c.1745G>A), located in coding exon 11 of the LMNA gene, results from a G to A substitution at nucleotide position 1745. The arginine at codon 582 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple unrelated individuals with atypical familial partial lipodystrophy (FPLD) in both the heterozygous and homozygous state, with severity of the disease correlated with zygosity (Garg A et al. J Clin Endocrinol Metab, 2001 Jan;86:59-65; Boschmann M et al. J Clin Endocrinol Metab, 2010 Apr;95:1634-43; Akinci B et al. Metabolism, 2017 07;72:109-119; Patni N et al. J Clin Endocrinol Metab, 2019 04;104:1099-1108; Soyaltin UE et al. Clin Diabetes Endocrinol, 2020 Jul;6:13). This variant has also been reported to segregate with disease (Speckman RA et al. Am J Hum Genet, 2000 Apr;66:1192-8; Akinci B et al. Metabolism, 2017 07;72:109-119). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.