ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1318G>A (p.Val440Met) (rs121912493)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000552191 SCV000657800 uncertain significance Charcot-Marie-Tooth disease, type 2 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 440 of the LMNA protein (p.Val440Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with mandibuloacral dysplasia (PMID: 17848409). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has also been reported in the heterozygous state in an individual affected with dilated cardiomyopathy (PMID: 19875404) and in the compound heterozygous state in an individual affected with a severe form of familial partial lipodystrophy (FPLD) (PMID: 10999845). ClinVar contains an entry for this variant (Variation ID: 14520). Experimental studies have found that cell lines carrying this missense change in the compound heterozygous state display altered nuclear morphology and heterochromatin organization (PMID: 17848409). A yeast two-hybrid screen has found that this missense change leads to a decrease in the number of LMNA interaction partners, but the functional significance of this observation is not known (PMID: 24623722). 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.
Molecular Genetics Laboratory,London Health Sciences Centre RCV001172618 SCV001335681 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Color RCV001186220 SCV001352586 uncertain significance Cardiomyopathy 2018-11-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001264435 SCV001442586 uncertain significance not specified 2020-10-27 criteria provided, single submitter clinical testing Variant summary: LMNA c.1318G>A (p.Val440Met) results in a conservative amino acid change located in the Lamin tail domain (IPR001322) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248838 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1318G>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy (e.g. Moller_2009, Sousa_2019, Martins_2019), but also unaffected family members (e.g. Moller_2009). The variant has also been reported in a compound heterozygous state with a pathogenic variant in an individual diagnosed with Mandibuloacral dysplasia type A (MADA), consistent with an autosomal recessive pattern of inhertiance for this disease (e.g. Lombardi_2007). Other reports in the literature include the variant in a compound heterozygous state with another pathogenic variant in LMNA in an individual with a severe form of Dunnigan-type partial lipodystrophy (FPLD, Hegele_2000), leading the authors to suggest that the variant may modify this phenotype, and in an individual with Hutchinson-Gilford Progeria Syndrome (HGPD, Zhang_2016). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Several publications report experimental evidence evaluating an impact on protein function, however, do not allow convincing conclusions about the variant effect (e.g. Nitta_2006, Lombardi_2007, Dittmer_2014). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as uncertain significance. Based on the evidence outlined above, until additional information becomes available, the variant was classified as uncertain significance.
OMIM RCV000015617 SCV000035882 pathogenic Mandibuloacral dysplasia with type A lipodystrophy, atypical 2007-11-01 no assertion criteria provided literature only
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057268 SCV000088381 not provided not provided no assertion provided not provided

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