Submissions for variant NM_170707.4(LMNA):c.398G>A (p.Arg133Gln)

gnomAD frequency: 0.00001  dbSNP: rs60864230

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182356	SCV000234669	likely pathogenic	not provided	2022-09-12	criteria provided, single submitter	clinical testing	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)
Invitae	RCV000204542	SCV000262236	pathogenic	Charcot-Marie-Tooth disease type 2	2023-11-17	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001096448	SCV001252660	uncertain significance	Lethal tight skin contracture syndrome	2018-01-12	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001096449	SCV001252661	uncertain significance	Lipoatrophy with Diabetes, Hepatic Steatosis, Hypertrophic Cardiomyopathy, and Leukomelanodermic Papules	2018-01-12	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001098184	SCV001254534	uncertain significance	Emery-Dreifuss muscular dystrophy 2, autosomal dominant	2018-01-12	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001098185	SCV001254535	uncertain significance	Mandibuloacral dysplasia with type A lipodystrophy	2018-01-12	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001098186	SCV001254536	uncertain significance	Emery-Dreifuss muscular dystrophy	2018-01-12	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001098187	SCV001254537	uncertain significance	Charcot-Marie-Tooth disease type 2B1	2018-01-12	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001098188	SCV001254538	uncertain significance	Congenital muscular dystrophy due to LMNA mutation	2018-01-12	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001098189	SCV001254539	uncertain significance	Familial partial lipodystrophy, Dunnigan type	2018-01-12	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001098190	SCV001254540	uncertain significance	Hutchinson-Gilford syndrome	2018-01-12	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001098191	SCV001254541	uncertain significance	Dilated cardiomyopathy 1A	2018-01-12	criteria provided, single submitter	clinical testing	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.
Color Diagnostics, LLC DBA Color Health	RCV001191911	SCV001359845	uncertain significance	Cardiomyopathy	2023-05-03	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002372114	SCV002626152	uncertain significance	Cardiovascular phenotype	2023-07-13	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000182356	SCV003916510	likely pathogenic	not provided	2023-02-01	criteria provided, single submitter	clinical testing	LMNA: PM1, PM2, PM5, PS4:Moderate, PS3:Supporting
All of Us Research Program, National Institutes of Health	RCV003996714	SCV004840502	uncertain significance	Primary dilated cardiomyopathy	2023-10-02	criteria provided, single submitter	clinical testing	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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000182356	SCV000280182	likely pathogenic	not provided	2015-10-19	no assertion criteria provided	clinical testing	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000182356	SCV001739627	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000182356	SCV001955981	uncertain significance	not provided		no assertion criteria provided	clinical testing