Submissions for variant NM_170707.4(LMNA):c.1718C>T (p.Ser573Leu)

gnomAD frequency: 0.00011  dbSNP: rs60890628

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041329	SCV000065022	uncertain significance	not specified	2020-12-18	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ser573Leu variant in LMNA has been identified in individuals across multiple phenotypes: in the heterozygous state in 5 individuals with DCM, including 1 who had likely pathogenic variant in another gene that could explain their disease (Taylor 2003 PMID:12628721, Pasotti 2008 PMID:18926329, Dal Ferro 2017 PMID: 28416588, LMM data) and segregated with disease in 3 affected relatives from 2 families (Pasotti 2008, PMID:18926329). It has also been reported in 2 individuals with HCM (LMM data), 1 individual with Brugada syndrome (Proost 2017 PMID :28341588), 5 individuals with Limb-Girdle or Emery-Dreifuss muscular dystrophy (Benedetti 2007 PMID: 17377071, Bernasconi 2018 PMID: 29693488), and 1 individual with familial partial lipodystrophy (Lanktree 2007 PMID: 17250669). In the homozygous state, this variant has been reported in an individual with arthropathy, tendinous calcinosis, and progeroid features (Van Esch 2006 PMID: 16278265). This variant segregated with DCM in 3 affected relatives from 2 families (Pasotti 2008, PMID:18926329). In addition, this variant has also been reported by other clinical laboratories in ClinVar (Variation ID 14517) and has also been identified in 0.04% (4/10102) of Ashekanzi Jewish chromosomes, 0.04% (13/35168) of Latino chromosomes, and in 0.01% (14/121150) of European chromosomes, including one homozygote, by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant does not impact protein function (Nitta 2006 PMID 16809772, Van Tienen PMID 30420677); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of this variant is uncertain, its frequency in the general population suggests that it is more likely to be benign. ACMG/AMP Criteria Applied: PP1, BS1.
GeneDx	RCV000057351	SCV000491119	uncertain significance	not provided	2022-08-26	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in individuals with DCM, HCM, arrhythmia, familial partial lipodystrophy subtype 2, and in a patient with a Limb-girdle muscular dystrophy phenotype with no cardiac involvement (Pasotti et al., 2008; Francisco et al., 2017; Taylor et al., 2003; Lanktree et al., 2007; Benedetti et al., 2007; Zhang et al., 2016; Proost et al., 2017; van Tienen, 2019; Quaio et al., 2020; Gigli et al., 2019); Reported previously in a patient with HCM who also had a variant reported in MYL2 that was thought to be responsible for the phenotype; complete segregation information was unavailable (De Bortoli et al., 2020); Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID# 14517; ClinVar); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least one homozygous individual in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24846508, 28341588, 19875478, 18926329, 30420677, 17377071, 24503780, 27707468, 16636128, 18031308, 12628721, 28874324, 28663758, 28416588, 29800922, 29764566, 16809772, 32799420, 32746448, 10939567, 15475483, 31525256, 31514951, 33258288, 17250669, 33916827, 16278265, 32004434, 35535697, ZhaoY2022, 32616434, 29693488)
Eurofins Ntd Llc (ga)	RCV000057351	SCV000700905	uncertain significance	not provided	2017-11-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617932	SCV000738025	uncertain significance	Cardiovascular phenotype	2024-01-12	criteria provided, single submitter	clinical testing	The p.S573L variant (also known as c.1718C>T), located in coding exon 11 of the LMNA gene, results from a C to T substitution at nucleotide position 1718. The serine at codon 573 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals with diseases on the laminopathy spectrum, including individuals with dilated cardiomyopathy (DCM), at least one of whom also had variants in other cardiac-related genes (Taylor MR et al. J. Am. Coll. Cardiol., 2003 Mar;41:771-80; Pasotti M et al. J. Am. Coll. Cardiol., 2008 Oct;52:1250-60; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Dal Ferro M et al. Heart, 2017 11;103:1704-1710), as well as individuals with unspecified primary electrical disease (Proost D et al. J Mol Diagn, 2017 05;19:445-459), familial partial leukodystrophy type 2 (Lanktree M et al. Clin. Genet., 2007 Feb;71:183-6), limb-girdle dystrophy (Benedetti S et al. Neurology, 2007 Sep;69:1285-92; Bernasconi P et al. Nucleus, 2018 01;9:292-304), and Emery-Dreifuss muscular dystrophy (Bernasconi P et al. Nucleus, 2018 01;9:292-304). This variant was also detected as heterozygous in an individual with hypertrophic cardiomyopathy (HCM) and metabolic syndrome (Francisco ARG et al. Rev Port Cardiol, 2017 Sep;36:669.e1-669.e4). In addition, this variant was described as homozygous in an individual with a novel arthropathy phenotype demonstrating progeroid features, generalized lipodystrophy, and sclerodermatous skin (Van Esch H et al. J. Clin. Endocrinol. Metab., 2006 Feb;91:517-21); this patient's heterozygous son and presumed obligate carrier mother were unaffected with no reported cardiac findings. This variant has also been detected in cohorts not selected for the presence of LMNA-related disease; however, details were limited (Kasak L et al. Hum Reprod. 2022 Jun;37(7):1652-1663; Quaio CRDC et al. Am J Med Genet C Semin Med Genet. 2020 Dec;184(4):955-964). In one experimental study, this alteration was found to restore responsiveness in LMNA-deficient fibroblasts (Nitta RT et al. Mol Cell Biol, 2006 Jul;26:5360-72). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000653881	SCV000775771	likely benign	Charcot-Marie-Tooth disease type 2	2024-01-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188887	SCV001356059	uncertain significance	Cardiomyopathy	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 573 of the lamin A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant can restore LMNA protein function in LMNA-deficient fibroblasts (PMID: 16809772), and does not change lamina organization or the interaction with chromatin (Banerjee et al. 2020, https://doi.org/10.1101/2020.05.01.071803). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 12628721, 18926329, 28416588, 32616434, 32746448, 35026164), in an individual affected with cardiac arrhythmia (PMID: 28341588), in an individual with a complex phenotype including hypertrophic cardiomyopathy, left ventricular outflow tract obstruction and metabolic syndrome (PMID: 28874324), in an individual affected with Brugada syndrome (PMID: 35026164), and in an individual affected with hypertrophic cardiomyopathy who also carried a pathogenic variant in the MYL2 gene that could explain the observed phenotype (PMID: 32004434). This variant has also been reported in an individual with lipodystrophy (PMID: 17250669), in an individual affected with limb-girdle muscular dystrophy without cardiac involvement (PMID: 17377071), in an individual with progeroid features with no evidence of cardiomyopathy (PMID: 16278265), and in an individual affected with type 2 familial partial lipodystrophy (PMID: 33916827). However, this variant has also been identified in 38/271142 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248900	SCV001422587	benign	Familial partial lipodystrophy	2020-01-22	criteria provided, single submitter	curation	The p.Ser573Leu variant in LMNA has been reported in 1 European individual with familial partial lipodystrophy (PMID: 17250669), but has been identified in 0.04% (4/10102) of Ashkenazi Jewish chromosomes and other populations at slightly lesser frequencies by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs60890628). 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: 14517). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as benign for familial partial lipodystrophy in an autosomal dominant manner based on its frequency in the general population. ACMG/AMP Criteria applied: BA1 (Richards 2015).
Athena Diagnostics	RCV000057351	SCV001476537	likely benign	not provided	2020-06-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000057351	SCV001715575	uncertain significance	not provided	2019-11-11	criteria provided, single submitter	clinical testing
Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo	RCV002221478	SCV001977120	uncertain significance	Charcot-Marie-Tooth disease type 2B1	2021-07-20	criteria provided, single submitter	research	The c.1718C> T (p.Ser573Leu) variant in the LMNA gene has been described in the literature as both heterozygous and homozygous in several individuals with a variety of phenotypes (PMID: 16278265; PMID: 12628721; PMID: 28874324; PMID: 18926329; PMID: 17250669; PMID: 28416588; PMID: 29693488; PMID: 30420677; PMID: 16809772). This variant is deposited in the ClinVar, but there is a conflict of interpretation (Variation ID: 14517), 1 star. This variant, also known as p.Ser543Leu, replaces Serine with Leucine at codon 573 (543) of the LMNA protein that is highly conserved across different species. This variant is present in the gnomAD (rs60890628; 0.01401e-2) and ABraOM (rs60890628; 0.000427) population database at reasonable frequency, including 1 homozygote. Our lab found it once, in heterozygous, in a 10-years-old male with a mild CMT2 phenotype and mild diffuse muscle weakness, predominantly distal, but also affecting the face who also have a variant, classified as likely pathogenic, in the EMD gene (ClinVar ID: SCV001976635). Interestingly, a study published in 2007 described a single family with high intrafamilial phenotypic heterogeneity that had variants in both genes (LMNA + EMD) and demonstrated that alterations in these two genes likely have a synergistic effect on both the phenotype and expression of laminin proteins A and C (PMID: 17536044). However, we do not know its real effect on our patient's phenotype. Therefore, it has been classified as a variant of uncertain significance (VUS).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041329	SCV002511981	uncertain significance	not specified	2022-04-28	criteria provided, single submitter	clinical testing	Variant summary: LMNA c.1718C>T (p.Ser573Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 239760 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in LMNA causing Cardiomyopathy (0.00015 vs 0.00025), allowing no conclusion about variant significance. c.1718C>T has been reported in the literature in individuals affected with different phenotypes including, dilated cardiomyopathy (Taylor_2003, Pasotti_2008, Pugh_2014, Dal Ferro_2017, Burstein_2021), hypertrophic cardiomyopathy (Francisco_2017), long QT syndrome (van Tienen_2019), limb-girdle muscular dystrophy (Benedetti_2007, Bernasconi_2018), familial partial lipodystrophy (Lanktree_2007), and Emery-Dreifuss muscular dystrophy (Bernasconi_2018), but it was also reported in unaffected individuals (e.g. Taylor_2003, Van Esch_2006). Furthermore, the variant was reported in a homozygous patient affected with arthropathy, tendinous calcinosis, and progeroid features (Van Esch_2006). These reports do not provide unequivocal conclusions about association of the variant with disease. At least one co-occurrence with a pathogenic variant has been reported in a patient affected with dilated cardiomyopathy (TTN c.49511delG, p.Gly16504GlufsX12; Pugh_2014). Experimental evidence demonstrated the variant can restore protein function in LMNA-deficient cells and generally confer normal nuclear morphology (Nitta_2006, van Tienen_2019). However, this evidence does not allow convincing conclusions about the variant effect. Ten ClinVar submitters (evaluation after 2014) cite the variant with conflicting assessments: uncertain significance (n=7), benign/likely (n=2), likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000057351	SCV003814686	uncertain significance	not provided	2022-09-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000057351	SCV004124993	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing	LMNA: PP1
OMIM	RCV000015612	SCV000035877	pathogenic	Dilated cardiomyopathy 1A	2007-02-01	no assertion criteria provided	literature only
OMIM	RCV000015613	SCV000035878	pathogenic	Mandibuloacral dysplasia with type A lipodystrophy, atypical	2007-02-01	no assertion criteria provided	literature only
OMIM	RCV000015614	SCV000035879	pathogenic	Familial partial lipodystrophy, Dunnigan type	2007-02-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057351	SCV000088464	not provided	not provided		no assertion provided	not provided
Clinical Genetics, Academic Medical Center	RCV000057351	SCV001979124	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000057351	SCV001979692	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000057351	SCV002036352	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laan Lab, Human Genetics Research Group, University of Tartu	RCV000015612	SCV002538608	likely pathogenic	Dilated cardiomyopathy 1A	2021-05-01	flagged submission	research
Department of Medical Genetics, National Institute of Health	RCV002509159	SCV002547317	pathogenic	Congenital muscular dystrophy due to LMNA mutation	2022-04-15	no assertion criteria provided	clinical testing	We report the case of a 7-month-old Moroccan male child presenting with congenital hypotonia, muscle weakness, dropped head syndrome, and normal heart function. In the literature, the NM_170707.4(LMNA):c.1718C>T (p.Ser573Leu) (dbSNP: rs60890628) variant in exon 11 of the LMNA gene has been identified in individuals across multiple forms: In the heterozygous state with dilated cardiomyopathy (Taylor 2003 PMID:12628721, Pasotti 2008 PMID:18926329, Dal Ferro 2017 PMID: 28416588, Burstein 2021 PMID: 32746448), hypertrophic cardiomyopathy (Francisco 2017 PMID: 28874324). Moreover, patients with Limb-Girdle or Emery-Dreifuss muscular dystrophy (Benedetti 2007 PMID: 17377071, Bernasconi 2018 PMID: 29693488), and familial partial lipodystrophy (Lanktree 2007 PMID: 17250669) were also reported. In the homozygous state, this variant has been reported in an individual with arthropathy, tendinous calcinosis, and progeroid features (Van Esch 2006 PMID: 16278265) with no cardiac involvement. The heterozygous missense c.1718C>T variant was not found in 138 Moroccan clinical exomes (in-house database), and It was classified as a pathogenic variant with PP5, PM1, PM2, PP2, PP3, and PS2 rules according to the recommendations of ACMG/AMP. We report for the first time a new phenotype associated with a de novo variant in exon 11 of the LMNA gene: Congenital muscular dystrophy. We assume that it is a strong candidate variation responsible for the phenotype in our patient.