1-156138507-C-T

Variant names:

• chr1-156138507-C-T
• rs60890628
• NM_170707.4:c.1718C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:15 B:3 O:1
• Conservation: PhyloP100: 3.59
• Publications: 34 publications found

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]

LMNA Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
• familial partial lipodystrophy, Dunnigan type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• Hutchinson-Gilford progeria syndrome

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• restrictive dermopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: G2P
• Emery-Dreifuss muscular dystrophy 2, autosomal dominant

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• atrioventricular block

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• heart-hand syndrome, Slovenian type

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• Charcot-Marie-Tooth disease type 2B1

  Inheritance: AR, AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Emery-Dreifuss muscular dystrophy 3, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mandibuloacral dysplasia with type A lipodystrophy

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• atrial fibrillation

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• atypical Werner syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy due to LMNA mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal restrictive dermopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LMNA-related cardiocutaneous progeria syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Emery-Dreifuss muscular dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal semi-dominant severe lipodystrophic laminopathy

  Inheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21791962).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1718C>T	p.Ser573Leu	missense_variant	Exon 11 of 12	ENST00000368300.9	NP_733821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1718C>T	p.Ser573Leu	missense_variant	Exon 11 of 12	1	NM_170707.4	ENSP00000357283.4

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000146 AC: 35 AN: 239760 AF XY: 0.000137

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000379

Gnomad ASJ exome AF: 0.000408

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000644 AC: 94 AN: 1460110 Hom.: 1 Cov.: 32 AF XY: 0.0000564 AC XY: 41 AN XY: 726380

African (AFR) AF: 0.0000299 AC: 1 AN: 33462

American (AMR) AF: 0.000269 AC: 12 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26092

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39674

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52262

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5724

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111770

Other (OTH) AF: 0.000133 AC: 8 AN: 60324

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74372

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.000262 AC: 4 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.0000909 AC: 11

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:15 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:9 Benign:1 Other:1

Sep 22, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LMNA c.1718C>T; p.Ser573Leu variant (rs60890628) is reported in the literature in individuals and families with dilated cardiomyopathy, hypertrophic cardiomyopathy, familial partial lipodystrophy, limb girdle muscular dystrophy, Charcot-Marie-Tooth disease, arrhythmia, and Emery-Dreifuss muscular dystrophy (Benedetti 2007, Burstein 2021, Francisco 2017, Gigli 2019, McGurk 2023, Russo 2023, Taylor 2003, van Tienen 2019). However, this variant has also been identified in individuals who carry additional variants in cardiac-related genes (Burstein 2021, De Bortoli 2020), and in at least one clinically unaffected individual (Taylor 2003). The p.Ser573Leu variant is also reported in ClinVar (Variation ID: 14517). It is observed in the general population with an overall allele frequency of 0.01% (38/271142 alleles, including 1 homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.469). Based on available information, the clinical significance of this variant is uncertain at this time. References: Benedetti S et al. Phenotypic clustering of lamin A/C mutations in neuromuscular patients. Neurology. 2007 Sep 18;69(12):1285-92. PMID: 17377071. Burstein DS et al. Genetic variant burden and adverse outcomes in pediatric cardiomyopathy. Pediatr Res. 2021 May;89(6):1470-1476. PMID: 32746448. De Bortoli M et al. Novel Missense Variant in MYL2 Gene Associated With Hypertrophic Cardiomyopathy Showing High Incidence of Restrictive Physiology. Circ Genom Precis Med. 2020 Apr;13(2):e002824. PMID: 32004434. Francisco ARG et al. Complex phenotype linked to a mutation in exon 11 of the lamin A/C gene: Hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes. Rev Port Cardiol. 2017 Sep;36(9):669.e1-669.e4. English, Portuguese. PMID: 28874324. Gigli M et al. Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy. J Am Coll Cardiol. 2019 Sep 17;74(11):1480-1490. PMID: 31514951. McGurk KA et al. The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. Am J Hum Genet. 2023 Sep 7;110(9):1482-1495. PMID: 37652022. Russo V et al. Case report: Lamin A/C gene mutation in patient with drug-induced type 1 Brugada syndrome at high arrhythmic risk. Front Cardiovasc Med. 2023 Jan 10;9:1099508. PMID: 36704457. Taylor MR et al. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol. 2003 Mar 5;41(5):771-80. PMID: 12628721. van Tienen FHJ et al. Assessment of fibroblast nuclear morphology aids interpretation of LMNA variants. Eur J Hum Genet. 2019 Mar;27(3):389-399. PMID: 30420677. -

Nov 11, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LMNA: PP1 -

Jun 10, 2020

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 09, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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 (PMID: 17250669, 18926329, 28874324, 12628721, 17377071, 28341588, 30420677, 33258288, 31514951); 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 (PMID: 32004434); In silico analysis suggests 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, 15475483, 31525256, 31514951, 33258288, 37652022, 35535697, ZhaoY2022, 32616434, 29693488, 36704457, 17250669, 16278265, 32004434, 33916827, 10939567) -

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Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 14, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1A Pathogenic:2

Feb 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 01, 2021

Laan Lab, Human Genetics Research Group, University of Tartu

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

- -

not specified Uncertain:2

Jun 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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 estimated 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 (potentially) belonging to the laminopathies spectrum including, dilated cardiomyopathy (Taylor_2003, Pasotti_2008, Pugh_2014, Dal Ferro_2017, Burstein_2021, McGurk_2023), hypertrophic cardiomyopathy (Francisco_2017, De Bortoli_2020), long QT syndrome (van Tienen_2019), drug-induced type 1 Brugada syndrome (Russo_2023), 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). The following publications have been ascertained in the context of this evaluation (PMID: 17377071, 29693488, 32746448, 28416588, 28874324, 31514951, 17250669, 23062543, 16809772, 31383942, 18926329, 28341588, 24503780, 33258288, 12628721, 16278265, 30420677, 37652022, 36704457, 32004434). ClinVar contains an entry for this variant (Variation ID: 14517). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Dec 18, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Mandibuloacral dysplasia with type A lipodystrophy, atypical Pathogenic:1

Feb 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Congenital muscular dystrophy due to LMNA mutation Pathogenic:1

Apr 15, 2022

Department of Medical Genetics, National Institute of Health

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Familial partial lipodystrophy, Dunnigan type Pathogenic:1

Feb 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardiomyopathy Uncertain:1

Apr 12, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with leucine at codon 573 of the lamin A protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. 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 one individual affected with cardiac arrhythmia (PMID: 28341588), in one individual with a complex phenotype including hypertrophic cardiomyopathy, left ventricular outflow tract obstruction and metabolic syndrome (PMID: 28874324), in one individual affected with Brugada syndrome (PMID: 35026164), and in one 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 one individual with lipodystrophy (PMID: 17250669), in one individual affected with limb-girdle muscular dystrophy without cardiac involvement (PMID: 17377071), in one individual with progeroid features with no evidence of cardiomyopathy (PMID: 16278265), and in one 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

Jul 20, 2021

Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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). -

Cardiovascular phenotype Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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) (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 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 detected 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. Based on the available evidence, the clinical significance of this variant remains unclear. -

Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C1857829:Heart-hand syndrome, Slovenian type;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5399785:Mandibuloacral dysplasia with type A lipodystrophy;C5676942:Restrictive dermopathy 2;C5979868:Dilated cardiomyopathy 1A Uncertain:1

May 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2 Benign:1

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial partial lipodystrophy Benign:1

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
CardioboostCm	Benign	0.0015
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	.;D;.;.;.;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.22	T;T;T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.0	.;M;M;.;.;.
PhyloP100		3.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.78	N;N;N;N;N;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.010	D;D;D;D;D;D
Sift4G	Benign	0.10	T;T;T;D;T;T
Polyphen		0.95	P;D;.;.;.;.
Vest4		0.59
MVP		0.95
MPC		0.37
ClinPred		0.051	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.74
Mutation Taster		=51/49	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs60890628; hg19: chr1-156108298; COSMIC: COSV61542858; COSMIC: COSV61542858;