rs60890628
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_170707.4(LMNA):c.1718C>T(p.Ser573Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000695 in 1,612,344 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S573S) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000064 ( 1 hom. )
Consequence
LMNA
NM_170707.4 missense
NM_170707.4 missense
Scores
1
11
6
Clinical Significance
Conservation
PhyloP100: 3.59
Genes affected
LMNA (HGNC:6636): (lamin A/C) The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, LMNA
BP4
?
Computational evidence support a benign effect (MetaRNN=0.21791962).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.1718C>T | p.Ser573Leu | missense_variant | 11/12 | ENST00000368300.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.1718C>T | p.Ser573Leu | missense_variant | 11/12 | 1 | NM_170707.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152234Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000146 AC: 35AN: 239760Hom.: 1 AF XY: 0.000137 AC XY: 18AN XY: 131550
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GnomAD4 exome AF: 0.0000644 AC: 94AN: 1460110Hom.: 1 Cov.: 32 AF XY: 0.0000564 AC XY: 41AN XY: 726380
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GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74372
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:13Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:8Benign:1Other:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 14, 2017 | - - |
| not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 10, 2020 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 26, 2022 | 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) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2023 | LMNA: PP1 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 11, 2019 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 22, 2022 | - - |
Dilated cardiomyopathy 1A Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2007 | - - |
| Likely pathogenic, flagged submission | research | Laan Lab, Human Genetics Research Group, University of Tartu | May 01, 2021 | - - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 28, 2022 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 18, 2020 | 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. - |
Mandibuloacral dysplasia with type A lipodystrophy, atypical Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2007 | - - |
Congenital muscular dystrophy due to LMNA mutation Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Medical Genetics, National Institute of Health | Apr 15, 2022 | 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. - |
Familial partial lipodystrophy, Dunnigan type Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2007 | - - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 05, 2023 | 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. - |
Charcot-Marie-Tooth disease type 2B1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo | Jul 20, 2021 | 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). - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 12, 2024 | 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. - |
Charcot-Marie-Tooth disease type 2 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | - - |
Familial partial lipodystrophy Benign:1
| Benign, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;D
Sift4G
Benign
T;T;T;D;T;T
Polyphen
P;D;.;.;.;.
Vest4
MVP
MPC
0.37
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at