ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.350A>G (p.Lys117Arg) (rs397517901)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041346 SCV000065039 uncertain significance not specified 2019-06-28 criteria provided, single submitter clinical testing 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000324940 SCV000345189 likely pathogenic not provided 2016-09-14 criteria provided, single submitter clinical testing
Invitae RCV000653882 SCV000775772 uncertain significance Charcot-Marie-Tooth disease, type 2 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 117 of the LMNA protein (p.Lys117Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs397517901, ExAC 0.03%). This variant has been reported in several individuals affected with dilated cardiomyopathy (PMID: 23183350, 23328570, 26752647, 27532257). This variant has been reported in individuals in the Universal Mutation Database (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 48063). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000853426 SCV000996337 uncertain significance Hypertrophic cardiomyopathy 2017-03-17 criteria provided, single submitter research 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'.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000324940 SCV001147457 uncertain significance not provided 2019-02-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001098090 SCV001254432 benign Emery-Dreifuss muscular dystrophy 2017-08-24 criteria provided, single submitter clinical testing 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001098091 SCV001254433 benign Hutchinson-Gilford syndrome 2017-08-24 criteria provided, single submitter clinical testing 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001098092 SCV001254434 uncertain significance Lipoatrophy with Diabetes, Hepatic Steatosis, Hypertrophic Cardiomyopathy, and Leukomelanodermic Papules 2017-08-24 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001098093 SCV001254435 uncertain significance Charcot-Marie-Tooth disease type 2B1 2017-08-24 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001098094 SCV001254436 uncertain significance Congenital muscular dystrophy, LMNA-related 2017-08-24 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001007778 SCV001254437 uncertain significance Emery-Dreifuss muscular dystrophy 2, autosomal dominant 2017-08-24 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001098095 SCV001254438 uncertain significance Lethal tight skin contracture syndrome 2017-08-24 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001098096 SCV001254439 benign Familial partial lipodystrophy 2 2017-08-24 criteria provided, single submitter clinical testing 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001099881 SCV001256371 uncertain significance Dilated cardiomyopathy 1A 2017-08-24 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001099882 SCV001256372 uncertain significance Mandibuloacral dysplasia with type A lipodystrophy 2017-08-24 criteria provided, single submitter clinical testing 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.
Color RCV001182267 SCV001347660 uncertain significance Cardiomyopathy 2019-07-25 criteria provided, single submitter clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV001007778 SCV001167462 uncertain significance Emery-Dreifuss muscular dystrophy 2, autosomal dominant no assertion criteria provided research

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