ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1748C>T (p.Ser583Leu) (rs59601651)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000057354 SCV000234710 uncertain significance not provided 2016-12-20 criteria provided, single submitter clinical testing The Ser583Leu mutation in the LMNA gene has been reported in patients with lipodystrophy without apparent cardiomyopathy (Savage D et al., 2004). Savage et al. identified the Ser583Leu mutation in three unrelated Caucasian families with familial partial lipodystrophy (Ko?bberling-type FPL), while it was not detected in 200 control alleles. Also, mutations in nearby residues (Arg582His, Arg584His) have been reported to cause lipodystrophy (Savage D et al., 2004), further supporting the functional importance of this region of the protein. Ser583Leu results in a non-conservative amino acid substitution of a neutral, polar Serine with a non-polar Leucine at a residue that is conserved across species. Furthermore, the Ser583Leu mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.Therefore, the presence of the Ser583Leu mutation indicates an increased risk to develop DCM and/or other LMNA-related disorders. However, other genetic and environmental factors influence disease expression and severity, and some mutation carriers may never become symptomatic.
Ambry Genetics RCV000618100 SCV000735752 uncertain significance Cardiovascular phenotype 2017-03-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000653858 SCV000775748 uncertain significance Charcot-Marie-Tooth disease, type 2 2018-09-24 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 583 of the LMNA protein (p.Ser583Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs59601651, ExAC 0.002%). This variant has been reported to segregate with familial partial lipodystrophy (FPL) in several families, being in combination with another LMNA variant (p.Thr528Met) in one of them diagnosed with typical Dunnigan-type FPL (PMID: 15298354). ClinVar contains an entry for this variant (Variation ID: 66864). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057354 SCV000088467 not provided not provided no assertion provided not provided

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