ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1487C>T (p.Thr496Met) (rs200466188)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235878 SCV000293193 uncertain significance not provided 2015-10-12 criteria provided, single submitter clinical testing The T496M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T496M variant 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. The T496M 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 that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (L489P, W498R, W498C) have been reported in the Human Gene Mutation Database in association with LMNA-associated disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Invitae RCV000653862 SCV000775752 uncertain significance Charcot-Marie-Tooth disease, type 2 2017-10-17 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 496 of the LMNA protein (p.Thr496Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs200466188, ExAC 0.009%). This variant has not been reported in the literature in individuals with LMNA-related disease. ClinVar contains an entry for this variant (Variation ID: 245964). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000681642 SCV000809088 uncertain significance Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Benign scapuloperoneal muscular dystrophy with cardiomyopathy; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy 2; Mandibuloacral dysostosis; Limb-girdle muscular dystrophy, type 1B; Lethal tight skin contracture syndrome; Congenital muscular dystrophy, LMNA-related; Emery-Dreifuss muscular dystrophy 3, autosomal recessive 2018-04-10 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000235878 SCV000925153 uncertain significance not provided 2015-12-01 no assertion criteria provided provider interpretation

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