ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1366A>G (p.Asn456Asp)

dbSNP: rs267607599
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000465598 SCV000548861 pathogenic Charcot-Marie-Tooth disease type 2 2018-01-12 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 456 of the LMNA protein (p.Asn456Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in a population databases (rs267607599), however, there is no reported allele frequency. This variant has been reported in 2  individuals affected with early onset myopathy and Emery-Dreifuss muscular dystrophy (PMID: 18551513, 21520333). This variant has been shown to arise de novo in individuals affected with early onset myopathy (PMID: 18551513). ClinVar contains an entry for this variant (Variation ID: 66811). Different missense substitutions at this codon (p.Asn456His, p.Asn456Ile, p.Asn456Lys) are reported to be deleterious (PMID: 24623722, 10939567, 18646565, 11973618, 21632249, 20980393, 22186027, 25996830). This indicates that the asparagine residue is important for lamin A/C protein function. 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 C15"). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000057277 SCV001248557 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000057277 SCV002552745 pathogenic not provided 2022-01-19 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 10939567, 27363342, 24375749, 24623722, 34240052, 32571898, 18551513)
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057277 SCV000088390 not provided not provided no assertion provided not provided

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