ClinVar Miner

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

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Total submissions: 11
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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 2018-07-16 criteria provided, single submitter clinical testing Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Classified in Jul 2015 and no new evidence: The p.Ser573Leu var iant in LMNA has been reported as homozygous in 1 individual with arthropathy, t endinous calcinosis, and progeroid features (Van Esch 2006) and as heterozygous in 1 individual with LGMD (Benedetti 2007), 1 individual with familial partial l ipodystrophy (Lanktree 2007), and 3 individuals with DCM as well as 1 affected family member (Taylor 2003, Pasotti 2008). The p.Ser573Leu variant has also been identified by our laboratory in 1 teenager with infantile DCM and 1 adult with HCM; however, the teenager also carried a likely pathogenic variant in another g ene (LMM unpublished data). It has also been identified in 9/57438 European chro mosomes by the Exome Aggregation consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs60890628). Computational prediction tools and conservation analysis d o not provide strong support for or against an impact to the protein. Although t he presence in affected individuals and low frequency in the general population suggests that this variant could play a role in disease, the clinical significan ce of the p.Ser573Leu variant is classified as uncertain since it is unclear if one variant could result in such a wide spectrum of phenotypes.
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 Insufficient evidence
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 RCV001188887 SCV001356059 uncertain significance Cardiomyopathy 2019-12-02 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,; 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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