ClinVar Genomic variation as it relates to human health

The LMNA Lys117Arg variant has been previously reported in multiple probands with various conditions. Botto et al., report this variant in 1 LVNC proband and their 2 daughters with mild LVNC (2011). It has also been reported in 2 DCM probands (Fontana M, et al., 2013; Pugh TJ, et al., 2014) it is important to note that one of the DCM probands also carried another pathogenic LMNA variant (Pugh TJ, et al., 2014). A patient with arthrogryposis features; contractures of hands and feet, myopathy, hypotonia, and dilated cardiomyopathy, was found to be harbouring both LMNA Lys117Arg and RIPK4 Val561Met in the homozygous form (Bayram Y, et al., 2016). The variant has also been reported in 2 Brugada syndrome patients (Pietrelli A, 2013) and in a Hispanic child with LVNC/DCM (LMM, ClinVar SCV000065039.4). Finally, we identified this variant in a male of Lebanese ethnicity with severe hypertrophic cardiomyopathy. The variant is present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at an allele frequency >0.00006 which is higher then expected for an inherited heart condition. Predictions from in silico tools are conflicting (SIFT "Tolerated"; PolyPhen-2 "Benign; MutationTaster "Disease causing"). In summary, based on the lack of evidence to associate a LMNA variant as a causative gene in HCM and the elevated allele frequency, we classify LMNA Lys117Arg as a variant of 'uncertain signifigance'.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 117 of the LMNA protein (p.Lys117Arg). This variant is present in population databases (rs397517901, gnomAD 0.02%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 2338570, 23183350, 26752647, 27532257). ClinVar contains an entry for this variant (Variation ID: 48063). 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. 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.

An LMNA c.350A>G (p.Lys117Arg) variant was identified. This variant has been published in the literature in relation to cardiac disease and arthrogryposis, but to our knowledge, has not been reported in association with diabetes. This variant has been reported in the ClinVar database as a variant of uncertain significance by numerous submitters. It is observed on 61/1,605,706 alleles in the general population (gnomAD v.4.0.0). including one homozygote. Computational predictors are uncertain as to the impact of this variant on LMNA function. Due to conflicting information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

The p.Lys117Arg variant in LMNA has been previously reported in 2 individuals with DCM (one of whom carried an additional pathogenic variant in LMNA), 1 individual with LVNC, 1 individual with DCM and LVNC, and in 2 individuals with unspecified cardiomyopathy and was found to segregate with disease in 2 affected family members with LVNC from 1 family (Botto 2011, Rijsingen 2013, Fontana 2013, LMM data). This variant was also identified in the homozygous state in 1 individual with DCM and arthrogryposis (Bayram 2016). It has been identified in 0.02% (6/29936) of South Asian chromosomes by gnomAD (http://gnomAD.broadinstitute.org/). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Lys117Arg variant is uncertain. ACMG/AMP Criteria Applied: None.

This missense variant replaces lysine with arginine at codon 117 of the lamin A/C proteins. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with dilated cardiomyopathy (PMID: 26752647, 2753225, 34935411). Additionally, this variant has been reported in three individuals who had been investigated by a cardiologist and/or affected with possible cardiac events (PMID: 23183350). This variant has been identified in 16/263490 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.

The p.K117R variant (also known as c.350A>G), located in coding exon 1 of the LMNA gene, results from an A to G substitution at nucleotide position 350. The lysine at codon 117 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in several dilated cardiomyopathy (DCM) and LMNA-related cardiomyopathy cohorts; however, clinical details were limited (Fontana M et al. JACC Cardiovasc Imaging. 2013;6:124-6; Pugh TJ et al. Genet. Med. 2014;16:601-8; Walsh R et al. Genet. Med. 2017;19:192-203; Peretto G et al. Ann Intern Med, 2019 10;171:458-463; Khan RS et al. J Am Heart Assoc. 2022 Jan;11(1):e022854). This variant was also detected in the homozygous state in an individual with arthrogryposis and DCM; however, the individual was homozygous for a missense variant in the RIPK4 gene (p.V561M) as well (Bayram Y et al. J. Clin. Invest. 2016;126:762-78). This amino acid position is well 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.

Variant summary: LMNA c.350A>G (p.Lys117Arg) results in a conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.8e-05 in 1605706 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in LMNA causing Cardiomyopathy (3.8e-05 vs 0.00025), allowing no conclusion about variant significance. c.350A>G has been reported in the literature in individuals affected with Cardiomyopathy (examples: Fontana_2013, Rijsingen_2013, Bayram_2016, Walsh_2017, Khan_2022, and McGurk_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At-least one publication has reported experimental evidence that this variant does not increase aggregation compared to WT protein in HEK 293 cells or C2C12 myoblasts (Anderson_2021). The following publications have been ascertained in the context of this evaluation (PMID: 34862408, 26752647, 23328570, 34935411, 37652022, 23183350, 27532257). ClinVar contains an entry for this variant (Variation ID: 48063). Based on the evidence outlined above, the variant was classified as uncertain significance.

This missense variant replaces lysine with arginine at codon 117 of the lamin A/C proteins. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with dilated cardiomyopathy (PMID: 26752647, 2753225, 34935411). Additionally, this variant has been reported in three individuals who had been investigated by a cardiologist and/or affected with possible cardiac events (PMID: 23183350). This variant has been identified in 16/263490 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.