ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1718C>T (p.Ser573Leu) (rs60890628)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 likely pathogenic not provided 2016-07-29 criteria provided, single submitter clinical testing The S573L variant in the LMNA gene has been reported previously in the heterozygous state in individuals with dilated cardiomyopathy, ventricular tachycardia and ventricular ectopy, familial partial lipodystrophy subtype 2, and in a patient with a Limb-girdle muscular dystrophy phenotype with no cardiac involvement (Pasotti et al., 2008; Taylor et al., 2003; Lanktree et al., 2007; Benedetti et al., 2007). The S573L variant has also been reported in the homozygous state in an individual with progeroid features with no cardiac involvement (Van Esch et al., 2006). The S573L variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S573L 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. This substitution occurs at a position where amino acids with similar properties to Serine are tolerated across species and is located within the LTD domain; in the Glubular caroxy-terminal tail . In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The S573L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000057351 SCV000700905 uncertain significance not provided 2017-11-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617932 SCV000738025 uncertain significance Cardiovascular phenotype 2019-04-04 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 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). However, this alteration has also been reported in individuals with no reported cardiac findings, including one with familial partial leukodystrophy type 2 (Lanktree M et al. Clin. Genet., 2007 Feb;71:183-6), one with limb-girdle dystrophy (Benedetti S et al. Neurology, 2007 Sep;69:1285-92), and one homozygous 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). Van Esch H et al, also described their homozygous patient's heterozygous son and presumed obligate carrier mother as unaffected with no reported cardiac findings. Based on data from gnomAD, the T allele has an overall frequency of approximately 0.014% (38/271142) including one homozygote. The highest observed frequency was 0.040% (4/10102) of Ashkenazi Jewish alleles. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000653881 SCV000775771 uncertain significance Charcot-Marie-Tooth disease, type 2 2019-11-13 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 573 of the LMNA protein (p.Ser573Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs60890628, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported as homozygous in an individual with an arthropathy syndrome, tendinous calcinosis, and progeroid features (PMID: 16278265), heterozygous in an individual affected with cardiac arrythmias (PMID: 28341588), in individuals affected with dilated cardiomyopathy (PMID: 12628721, 18926329, 28416588), in an individual with lipodystrophy (PMID: 17250669), in individuals affected with limb-girdle muscular dystrophy or Emery-Dreifuss muscular dystrophy (PMID: 17377071, 29693488), and in an individual with a complex phenotype including dyslipedemia, hypertrophic cardiomyopathy and left ventricular outflow tract obstruction (PMID: 28874324). This variant is also known as p.Ser543Leu in the literature. ClinVar contains an entry for this variant (Variation ID: 14517). Experimental studies have shown that this missense change can restore LMNA protein function in LMNA-deficient fibroblasts (PMID: 16809772, 30420677). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV001188887 SCV001356059 uncertain significance Cardiomyopathy 2019-12-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc 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
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 2 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
Broad Institute Rare Disease Group, Broad Institute RCV001248900 SCV001422587 benign Familial partial lipodystrophy 2020-01-22 no assertion criteria provided 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).

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