Submissions for variant NM_170707.4(LMNA):c.1634G>A (p.Arg545His) (rs142191737)

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000150955	SCV000198618	uncertain significance	not specified	2018-06-12	criteria provided, single submitter	clinical testing	The p.Arg545His variant in LMNA has been reported in at least 2 individuals with sudden death, 1 individual with partial lipodystrophy, 1 individual with lipody strophy and myopathy, 4 individuals with laminopathy-associated features, and se gregated with disease in 1 affected relative (LMM data, Houben 2013, van Rijsing en 2013, Chan 2016, Campuzano 2017, Neubauer 2017, Guillin-Amarelle 2018, Olaopa 2018). This variant has been reported in ClinVar (Variation ID: 163878) and has been identified in 0.05% (38/75898) of European chromosomes by the Genome Aggre gation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs142191737). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies provide some evidence that t he p.Arg545His variant may reduce sodium current (Olaopa 2018). However, these types of assays may not accurately represent biological function.Computational p rediction tools and conservation analysis do not provide strong support for or a gainst an impact to the protein. In summary, due to conflicting evidence and var iable phenotypes of affected individuals carrying the variant, the clinical sign ificance of the p.Arg545His variant is uncertain.ACMG/AMP criteria applied: PS3_ Moderate, PS4_Moderate.
GeneDx	RCV000505801	SCV000234709	likely pathogenic	not provided	2017-10-17	criteria provided, single submitter	clinical testing	A R545H variant that is likely pathogenic has been identified in the LMNA gene. The R545H variant in the LMNA gene was previously identified in one patient in a cohort of LMNA variant carriers who had known cardiac involvement or a family history of cardiac involvement (van Rijsingen et al., 2013). This variant has also been reported in a patient with lipodystrophy (Chan et al., 2016). Additionally, this variant has been reported in several individuals at GeneDx with various levels of cardiac involvement. The R545H variant is observed in 38/75898 (0.05%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The R545H variant is a conservative amino acid substitution, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Nevertheless, this substitution occurs at a position that is conserved among mammals and is located within the C-terminal tail domain. A variant in the same residue (R545C) has been reported in association with muscular dystrophy (Kandert et al., 2009). Additionally, missense variants in nearby residues (R541C, R541H, R541G) have been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014), further supporting the functional importance of this region of the protein.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000505801	SCV000338870	uncertain significance	not provided	2017-01-03	criteria provided, single submitter	clinical testing
Claritas Genomics	RCV000449630	SCV000537830	uncertain significance	Peripheral neuropathy	2016-08-22	criteria provided, single submitter	clinical testing
Invitae	RCV000468904	SCV000548853	uncertain significance	Charcot-Marie-Tooth disease, type 2	2019-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 545 of the LMNA protein (p.Arg545His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs142191737, ExAC 0.03%). This variant has been reported in multiple individuals affected with LMNA-related diseases (PMID: 22918509, 23183350, 27919367, 29791652). ClinVar contains an entry for this variant (Variation ID: 163878). 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"). The observation of a different missense substitution at this codon (p.Arg545Cys) in an affected individual suggests that this may be a clinically significant residue (PMID: 19589617). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000621850	SCV000736172	uncertain significance	Cardiovascular phenotype	2017-12-12	criteria provided, single submitter	clinical testing	Insufficient evidence
Color	RCV000771819	SCV000904524	uncertain significance	Cardiomyopathy	2020-01-27	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001100809	SCV001257349	benign	Emery-Dreifuss muscular dystrophy	2018-10-11	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	RCV001100810	SCV001257350	uncertain significance	Lipoatrophy with Diabetes, Hepatic Steatosis, Hypertrophic Cardiomyopathy, and Leukomelanodermic Papules	2018-10-11	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	RCV001101055	SCV001257624	uncertain significance	Emery-Dreifuss muscular dystrophy 2, autosomal dominant	2018-10-11	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	RCV001101056	SCV001257625	benign	Familial partial lipodystrophy 2	2018-10-11	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina	RCV001101057	SCV001257626	uncertain significance	Lethal tight skin contracture syndrome	2018-10-11	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	RCV001101058	SCV001257627	uncertain significance	Dilated cardiomyopathy 1A	2018-10-11	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	RCV001101059	SCV001257628	uncertain significance	Mandibuloacral dysplasia with type A lipodystrophy	2018-10-11	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	RCV001101060	SCV001257629	uncertain significance	Charcot-Marie-Tooth disease type 2B1	2018-10-11	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	RCV001101061	SCV001257630	uncertain significance	Hutchinson-Gilford syndrome	2018-10-11	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	RCV001101062	SCV001257631	uncertain significance	Congenital muscular dystrophy, LMNA-related	2018-10-11	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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000771819	SCV001333645	uncertain significance	Cardiomyopathy	2018-09-04	criteria provided, single submitter	clinical testing
Erich and Hanna Klessmann Institute for Cardiovascular Research and Development,Heart and Diabetes Center North Rhine-Westphalia	RCV000491650	SCV000298120	likely pathogenic	Dilated cardiomyopathy 1S	2016-05-01	no assertion criteria provided	clinical testing
Broad Institute Rare Disease Group,Broad Institute	RCV001248958	SCV001422752	uncertain significance	Lipodystrophy (disease)	2020-01-22	no assertion criteria provided	curation	The p.Arg545His variant in LMNA has been reported in 1 individual with lipodystrophy (PMID: 28074886), but has been identified in 0.05% (41/79748) of European (non-Finnish) chromosomes and other populations at lesser frequencies by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142191737). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 163878). In vitro functional studies provide some evidence that the p.Arg545His variant may slightly impact protein function (PMID: 22918509). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as p.Arg545His have been reported in association with disease in the literature and the variant is located in a region of LMNA that is thought to be essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 28663758). In summary, the clinical significance of the p.Arg545His variant is uncertain. ACMG/AMP Criteria applied: PP3, PS3_supporting, PM1_supporting, BA1 (Richards 2015).