ClinVar Genomic variation as it relates to human health

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 133 of the LMNA protein (p.Arg133Gln). This variant is present in population databases (rs60864230, gnomAD 0.002%). This missense change has been observed in individual(s) with myopathic gait, elevated CK, and muscle weakness and dilated cardiomyopathy (PMID: 27506821; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 200934). 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.Arg133 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11503164, 12629077, 12927431, 14615128, 16174718). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The p.R133Q variant (also known as c.398G>A), located in coding exon 2 of the LMNA gene, results from a G to A substitution at nucleotide position 398. The arginine at codon 133 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in an individual from a cardiovascular disease cohort (presumably with cardiomyopathy) who was treated for ventricular tachycardia and heart failure (Kumar S et al. J. Am. Coll. Cardiol., 2016 11;68:2299-2307; Kumar S et al. Circ Arrhythm Electrophysiol, 2016 08;9). This variant has also been detected in individuals reported to have dilated cardiomyopathy; however, details were limited and some reports may overlap (Cho S et al. Stem Cell Res. 2022 Jan;59:102657; Sayed N et al. Sci Transl Med. 2020 07;12(554)). 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.

Reported in association with cardiomyopathy and/or arrhythmia (Kumar et al., 2016a; Kumar et al., 2016b; Hou et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In vitro functional studies demonstrate endothelial cell dysfunction (Sayed et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10939567, 32727917, 34999423, 27884249, 27506821, 31980526)

This missense variant replaces arginine with glutamine at codon 133 of the lamin A/C proteins. 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). Induced pluripotent stem cells derived from a carrier individual exhibited endothelial cell dysfunction, as seen by impaired angiogenesis and nitric oxide production, suggesting that this variant may affect downstream signaling pathways in endothelial cells (PMID: 32727917). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 32727917, 34999423; communication with an external laboratory, ClinVar SCV000262236.7). This variant has also been reported in an individual affected with cardiomyopathy (PMID: 31980526), in an individual affected with ventricular tachycardia and death (PMID: 27506821), in an individual affected with arrhythmogenic right ventricular cardiomyopathy (communication with an external laboratory, ClinVar SCV000262236.7), and in an individual affected with arrhythmogenic right ventricular dysplasia (Elshafie, 2023). This variant has been identified in 3/282776 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon, p.Arg133Leu and p.Arg133Pro, are associated with autosomal recessive laminopathy phenotypes (Clinvar variation ID: 14488 and 14508), 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 autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This missense variant replaces arginine with glutamine at codon 133 of the lamin A/C proteins. 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). Induced pluripotent stem cells derived from a carrier individual exhibited endothelial cell dysfunction, as seen by impaired angiogenesis and nitric oxide production, suggesting that this variant may affect downstream signaling pathways in endothelial cells (PMID: 32727917). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 32727917, 34999423; communication with an external laboratory, ClinVar SCV000262236.7). This variant has also been reported in an individual affected with cardiomyopathy (PMID: 31980526), in an individual affected with ventricular tachycardia and death (PMID: 27506821), in an individual affected with arrhythmogenic right ventricular cardiomyopathy (communication with an external laboratory, ClinVar SCV000262236.7), and in an individual affected with arrhythmogenic right ventricular dysplasia (Elshafie, 2023). This variant has been identified in 3/282776 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon, p.Arg133Leu and p.Arg133Pro, are associated with autosomal recessive laminopathy phenotypes (Clinvar variation ID: 14488 and 14508), 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 autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

LMNA: PM1, PM2, PM5, PS4:Moderate, PS3:Supporting

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LMNA p.Arg133Gln When we initially reviewed the variant in 2011 it was discussed at a the Stanford Center for Inherited Cardiovascular Disease team meeting and we felt that the absence in controls, supporting segregation data, and other variants at the same codon were all sufficient to consider it likely pathogenic, though we would have preferred even more data supporting pathogenicity. Other variants in this gene have been associated with familial dilated cardiomyopathy, often with a higher incidence of conduction system disease, atrial arrhythmias, ventricular ectopy, and sudden death, all of which may occur prior to apparent LV dilatation or dysfunction. Variants in LMNA have also been associated with a wide range of other conditions, including Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy, both of which often have cardiac involvement. Other conditions associated with this gene include Charcot-Marie-Tooth disease, Dunnigan-type familial partial lipodystrophy and Hutchinson-Gilford progeria syndrome. These don't classically have cardiac involvement, but in some cases they do. Segregation data from our center includes a family in which the variant segregates with disease in three affected siblings (though two of the three siblings are identical twins) and the affected child of one of those siblings. Other variants at this same codon and the neighboring codon have been reported in association with disease. Brown et al (2001) reported p.Arg133Pro in an individual with limb-girdle muscular dystrophy who was diagnosed at 7 years of age. Her cardiac phenotype was noted to include atrial fibrillation and a pacemaker at 32 years of age. A different variant at this codon, p.Arg133Leu, has been reported in three unrelated cases with a progeroid phenotype (Chen et al 2003, Caux et al 2003). In one of those cases the variant was de novo. One of these individuals had hypertrophic cardiomyopathy and skeletal muscle hypertrophy. Lupsa et al 2010 reported a 9yo boy with lipodystrophy and p.Arg133Leu with dilated cardiomyopathy. Another variant at a neighboring codon (p.Ala132Pro) has been reported in association with dilated cardiomyopathy (Karkkainen et al 2006). p.Arg133Gln is a semi conservative amino acid change with a polar, positive Arginine replaced with a polar, neutral Glutamine. In silico analysis with PolyPhen2 predicts the variant to be possibly damaging. Many other variants in the same domain have been reported in association with dilated cardiomyopathy (Pasotti et al 2008). There is no variation at codon 133 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of October 16th, 2015). Mean coverage is >50.

The LMNA c.398G>A variant is predicted to result in the amino acid substitution p.Arg133Gln. This variant has been reported in families with cardiomyopathy (Kumar et al. 2016. PubMed ID: 27884249; Hou et al. 2020. PubMed ID: 31980526). Functional studies in induced pluripotent stem cells-derived endothelial cells from a patient with the p.Arg133Gln variant exhibit endothelial dysfunction (Sayed et al. 2020. PubMed ID: 32727917). Two different substitutions of the same amino acid (p.Arg133Leu and p.Arg133Pro) have been reported to be causative for lipodystrophy, Werner syndrome, and Emery-Driefuss muscular dystrophy (Jacob et al. 2005. PubMed ID: 16174718; Caux et al. 2003. PubMed ID: 12629077; Brown et al. 2001. PubMed ID: 11503164). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.