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

Total submissions: 17

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