Submissions for variant NM_170707.4(LMNA):c.1930C>T (p.Arg644Cys)

gnomAD frequency: 0.00117  dbSNP: rs142000963

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000057374	SCV000051400	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041340	SCV000065033	likely benign	not specified	2021-07-12	criteria provided, single submitter	clinical testing	The p.Arg644Cys variant in LMNA has been detected by our laboratory in 7 individuals with cardiomyopathy (2 with DCM, 1 with LVNC, 2 with HCM, 1 with an unspecified cardiomyopathy, and 1 with VFib and a T-wave inversion). Four of these patients had a very early age at onset (range birth to 7 years) and no family history, which is atypical for LMNA variants. The p.Arg644Cys variant has also been identified in a large number of individuals (>20) with a diverse range of clinical features consistent with laminopathy, isolated cardiomyopathy (DCM, ARVC, HCM) or Hallermann-Streiff syndrome, a rare genetic disorder with clinical overlap with some laminopathies (Speckman 2000 PMID: 10739751, Genschel 2001 PMID: 11180602, Csoka 2004 PMID: 15060110, Mercuri 2005 PMID: 15770669, Muntoni 2006 PMID: 16585054, Rankin 2008 PMID: 18478590, Pasotti 2008 PMID: 18926329, Perrot 2009 PMID: 18795223, Møller 2009 PMID: 19875404, Kortum 2011 PMID: 22570643, Scharner 2011 PMID: 20848652, Larsen 2012 PMID: 22177269, Quarta 2012 PMID: 22199124, Vasli 2012 PMID: 22526018, Hoyer 2014 PMID: 25025039). In addition, one study reported non-segregation with disease in 2 families (Mercuri 2005 PMID: PMID: 15770669). This variant has also been identified in 0.2% (251/126914) of European chromosomes, including 1 homozygote, chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein; however, in vitro functional studies indicate the variant may affect nuclear morphology (Csoka 2004 PMID: 15060110). In summary, the lack of segregation with disease, its population frequency, and the wide-spectrum of observed phenotypes sugests that the p.Arg644Cys variant is likely benign. ACMG/AMP Criteria applied: BS1, BS4.
GeneDx	RCV000041340	SCV000234713	uncertain significance	not specified	2017-08-25	criteria provided, single submitter	clinical testing	The R644C variant of uncertain significance in the LMNA gene has been reported multiple times in association with LMNA-related disorders, and demonstrates a wide phenotypic spectrum, variable severity, incomplete penetrance, and non-segregation (Genschel et al., 2001; Csoka et al., 2004; Mercuri et al., 2005; Muntoni et al., 2006; Rankin et al., 2008; Pasotti et al., 2008; Moller et al., 2009; Perrot et al., 2009; Scharner et al., 2011; Quarta et al., 2012; Vasli et al., 2012; Larsen et al., 2012; Hoyer et al., 2014; Cann et al., 2016). The R644C variant has been identified in individuals with isolated cardiomyopathy, laminopathies, Hallermann-Streiff syndrome, or Hutchinson-Gilford progeria syndrome, and also in asymptomatic relatives. Additionally, two studies reported that the R644C variant did not segregate with disease in two unrelated families (Mercuri et al., 2005; Muntoni et al., 2006). The Exome Aggregation Consortium (ExAC) reports R644C was observed in 106/63,724 alleles from individuals of Non-Finnish European and 27/16,410 alleles from individuals of South Asian ancestry, including one homozygote, indicating it may be a rare benign variant in these populations (Lek et al., 2016). It has been suggested that the extreme phenotypic variability caused by this pleiotropic LMNA variant could be due to either an altered methylation pattern or abnormal post-translational processing of prelamin A because R644C is located at the C-terminal end of lamin A/C close to the endoproteolytic cleavage site (Perrot et al., 2009; Capell et al., 2006). The R644C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved in mammals. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Ambry Genetics	RCV000245284	SCV000319734	likely benign	Cardiovascular phenotype	2021-11-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Eurofins Ntd Llc (ga)	RCV000041340	SCV000332002	likely benign	not specified	2016-01-26	criteria provided, single submitter	clinical testing
Invitae	RCV001084244	SCV000559827	likely benign	Charcot-Marie-Tooth disease type 2	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041340	SCV000699968	likely benign	not specified	2024-03-30	criteria provided, single submitter	clinical testing	Variant summary: PEX6 c.1930C>T (p.Arg644Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251362 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PEX6 causing Zellweger Syndrome (4.8e-05 vs 0.0019), allowing no conclusion about variant significance. c.1930C>T has been reported in the literature in compound heterozygosity with another PEX6 pathogenic variant in at-least two affected individuals from one family affected with Heimler syndrome (Ratbi_2015), who have been subsequently cited by others (example, Tucker_2020, and Gao_2019). These report(s) do not provide unequivocal conclusions about association of the variant with a complete defect in peroxisomal biogenesis as expected for Zellweger Syndrome. Both these individuals had normal persoxisomal parameters by biochemical analysis with a degree of peroxisomal mosaicism that was sensitive to temperature of cell culture prior to immunofluorescence analysis. To our knowledge, no experimental evidence demonstrating a variant specific impact on protein function has been reported. One database (OMIM) has submitted literature review based clinical-significance assessments for this variant to ClinVar after 2014 citing overlapping evidence utilized in the context of this evaluation and reporting a pathogenic outcome for Heimler syndrome. Based on the evidence outlined above, in the absence of additional clinical and functional assessment from multiple independent families supporting an unequivocal association to a defect in peroxisomal biogenesis, the variant was classified as uncertain significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000041340	SCV000747924	uncertain significance	not specified	2017-03-31	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000755679	SCV000883087	uncertain significance	Dilated cardiomyopathy 1A	2018-11-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771143	SCV000902953	likely benign	Cardiomyopathy	2018-03-16	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000057374	SCV001144440	benign	not provided	2019-01-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000057374	SCV001147469	uncertain significance	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV000144868	SCV001337374	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001174411	SCV001337549	benign	Monogenic diabetes	2018-11-02	criteria provided, single submitter	research	ACMG criteria: BS4 (lack of segregation in 15770669, 16585054), BS1 (0.2% MAF in EurNF), BS2 (two homozygotes in gnomAD), PS3 (reduces cleavage efficacy of prelaminA tail: 28663758, 22355414) [REVEL 0.608, PP3 (8), BP4 (2) = conflicting evidence, not using] = Benign
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000755679	SCV001367843	uncertain significance	Dilated cardiomyopathy 1A	2019-05-09	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,PP5.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771143	SCV002041917	benign	Cardiomyopathy	2019-09-12	criteria provided, single submitter	clinical testing
New York Genome Center	RCV002467497	SCV002764299	uncertain significance	Familial partial lipodystrophy, Dunnigan type	2023-03-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000057374	SCV003799578	uncertain significance	not provided	2022-03-08	criteria provided, single submitter	clinical testing	The LMNA c.1930C>T; p.Arg644Cys variant (rs142000963) is reported in the literature in individuals affected with cardiomyopathy and laminopathy LMNA-related disorders, including variable phenotypes, severity, penetrance, and segregation (Mercuri 2005, Muntoni 2006, Rankin 2008, Seidelmann 2017, Stehlikova 2017). This variant is also reported in ClinVar (Variation ID: 14527), and is found in the general population with an overall allele frequency of 0.12% (334/279890 alleles, including a single homozygote) in the Genome Aggregation Database. The arginine at codon 644 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.608). In vitro functional analyses of the variant protein show no significant effect on gap junctions or nuclear lamina integrity (De Vos 2011, Sun 2010), but other studies demonstrated impaired cleavage of lamin A (Barrowman 2012) and nuclear aberrations (Csoka 2004). While the high population frequency and lack of segregation with disease suggest that this is likely a benign variant, given the conflicting clinical and functional data, the significance of the p.Arg644Cys variant is uncertain at this time. References: Barrowman J et al. Requirements for efficient proteolytic cleavage of prelamin A by ZMPSTE24. PLoS One. 2012;7(2):e32120. PMID: 22355414. Csoka AB et al. Novel lamin A/C gene (LMNA) mutations in atypical progeroid syndromes. J Med Genet. 2004 Apr;41(4):304-8. PMID: 15060110. De Vos WH et al. Repetitive disruptions of the nuclear envelope invoke temporary loss of cellular compartmentalization in laminopathies. Hum Mol Genet. 2011 Nov 1;20(21):4175-86. PMID: 21831885. Mercuri E et al. Extreme variability of skeletal and cardiac muscle involvement in patients with mutations in exon 11 of the lamin A/C gene. Muscle Nerve. 2005 May;31(5):602-9. PMID: 15770669. Muntoni F et al. Disease severity in dominant Emery Dreifuss is increased by mutations in both emerin and desmin proteins. Brain. 2006 May;129(Pt 5):1260-8. PMID: 16585054. Rankin J et al. Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C. Am J Med Genet A. 2008 Jun 15;146A(12):1530-42. PMID: 18478590. Seidelmann SB et al. Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults. Circ Cardiovasc Genet. 2017 Feb;10(1):e001573. PMID: 28087566. Stehlikova K et al. Muscular dystrophies and myopathies: the spectrum of mutated genes in the Czech Republic. Clin Genet. 2017 Mar;91(3):463-469. PMID: 27447704. Sun LP et al. Connexin 43 remodeling induced by LMNA gene mutation Glu82Lys in familial dilated cardiomyopathy with atrial ventricular block. Chin Med J (Engl). 2010 Apr 20;123(8):1058-62. PMID: 20497714.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224100	SCV003920151	uncertain significance	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy, Dunnigan type; Mandibuloacral dysplasia with type A lipodystrophy; Congenital muscular dystrophy due to LMNA mutation; Emery-Dreifuss muscular dystrophy 3, autosomal recessive; Restrictive dermopathy 2	2021-03-30	criteria provided, single submitter	clinical testing	LMNA NM_170707.3 exon 11 p.Arg644Cys (c.1930C>T): This variant has been reported in the literature in several individuals with a wide spectrum of laminopathy phenotypes, including cardiomyopathies, cardioskeletal myopathies, atypical progeria, lipodystrophy, neuropathy, arthrogryposis, and hepatic stenosis (Genschel 2000 PMID:11180602, Csoka 2004 PMID:15060110, Mercuri 2005 PMID:15770669, Passotti 2008 PMID:18926329, Rankin 2008 PMID:18478590, Perrot 2009 PMID:18795223, Scharner 2011 PMID:20848652, Kortum 2011 PMID:22570643, De Vos 2011 PMID:21831885, Larsen 2012 PMID:22177269, Quarta 2013 PMID:22199124, Hoyer 2014 PMID:25025039, Parent 2015 PMID:25873806, Stehlikova 2017 PMID:27447704). This variant segregated with disease in at least 3 individuals, but did not segregate with disease in at least two others (Mercuri 2005 PMID:15770669, Parent 2015 PMID:25873806). This variant was also present in several asymptomatic relatives, indicating that it may have reduced penetrance. However, this variant is also present in 0.1% (251/126914) of European alleles in the Genome Aggregation Database, including one homozygote (https://gnomad.broadinstitute.org/variant/1-156108510-C-T), suggesting that it may be a common benign variant. This variant is present in ClinVar with conflicting interpretations (Variation ID:14527). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies have demonstrated partial inhibition of ZMPSTE24 cleavage with this variant (Barrowman 2012 PMID:22355414). However, multiple expression studies in fibroblast cultures of individuals with this variant have shown no effect on gap junctions and normal nuclear morphology (Sun 2010 PMID:20497714, De Vos 2011 PMID:21831885, van Tienen 2019 PMID:30420677). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
PreventionGenetics, part of Exact Sciences	RCV004528114	SCV004103796	uncertain significance	LMNA-related disorder	2023-04-07	criteria provided, single submitter	clinical testing	The LMNA c.1930C>T variant is predicted to result in the amino acid substitution p.Arg644Cys. The p.Arg644Cys variant has been identified in many unrelated individuals in association with different types of laminopathies, suggesting variable expressivity and incomplete penetrance (Rankin et al. 2008. PubMedID: 18478590). The phenotypic spectrum includes Emery-Dreifuss muscular dystrophy (Mercuri et al. 2005. PubMedID: 15770669), dilated cardiomyopathy (Genschel et al. 2001. PubMedID: 11180602; Parent et al. 2015. PubMedID: 25873806), and one patient with atypical progeria syndrome (Csoka et al. 2004. PubMedID: 15060110). However, the segregation data for the p.Arg644Cys variant is not conclusive (Mercuri et al. 2005. PubMedID: 15770669; Muntoni et al. 2006. PubMedID: 16585054). One study indicated that fibroblasts with the the p.Arg644Cys variant displayed normal nuclear morphology (van Tienen. 2019. PubMed ID: 30420677). This variant is reported in 0.20% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 1 homozygote (http://gnomad.broadinstitute.org/variant/1-156108510-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
OMIM	RCV000015626	SCV000035891	uncertain significance	Variant of unknown significance	2009-11-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057374	SCV000088487	not provided	not provided		no assertion provided	not provided
Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust	RCV000144868	SCV000172139	likely pathogenic	Charcot-Marie-Tooth disease	2013-11-01	no assertion criteria provided	research	Observed in two induviduals from two different families.
CSER _CC_NCGL, University of Washington	RCV000148602	SCV000190317	uncertain significance	Primary dilated cardiomyopathy	2014-06-01	no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000057374	SCV000925150	uncertain significance	not provided	2017-01-03	no assertion criteria provided	provider interpretation