ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1756G>A (p.Val586Met) (rs758048062)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000686535 SCV000814056 uncertain significance Charcot-Marie-Tooth disease, type 2 2019-05-10 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 586 of the LMNA protein (p.Val586Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs758048062, ExAC 0.002%). This variant has been reported in an individual affected with striated muscle laminopathy in the Universal Mutation Database (PMID: 10612827). 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: "Possibly 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.
Fulgent Genetics,Fulgent Genetics RCV000764984 SCV000896163 uncertain significance Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy 2; Mandibuloacral dysplasia with type A lipodystrophy; Lethal tight skin contracture syndrome; Congenital muscular dystrophy, LMNA-related; Emery-Dreifuss muscular dystrophy 3, autosomal recessive 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001251364 SCV001426936 uncertain significance not specified 2020-07-20 criteria provided, single submitter clinical testing Variant summary: LMNA c.1756G>A (p.Val586Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 243662 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1756G>A has been reported in the literature in at least one patient from the UMD laminopathy database (e.g. Florwick_2017). The variant was also detected in an individual who had exome sequencing (Park_2019). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000656219 SCV000678413 uncertain significance Wolff-Parkinson-White pattern 2017-07-14 no assertion criteria provided research This variant was identified in an individual with Wolff-Parkinson-White syndrome

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