ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.892C>T (p.Arg298Cys) (rs59885338)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000015590 SCV000255789 pathogenic Charcot-Marie-Tooth disease type 2B1 2014-11-18 criteria provided, single submitter clinical testing
Invitae RCV000653885 SCV000775775 pathogenic Charcot-Marie-Tooth disease, type 2 2018-06-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 298 of the LMNA protein (p.Arg298Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs59885338, ExAC 0.009%). This variant is a well known pathogenic founder mutation in North African countries and it has been reported to segregate with Charcot-Marie-Tooth type 2 in several affected familes (PMID: 18549403, 14607793, 17347251). ClinVar contains an entry for this variant (Variation ID: 14498). 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. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826146 SCV000967676 pathogenic Autosomal recessive axonal hereditary motor and sensory neuropathy 2018-03-02 criteria provided, single submitter clinical testing The p.Arg298Cys variant in LMNA has been reported as homozygous in at least 25 N orth African consanguineous families with clinical features of Charcot Marie Too th Disease variant 2B1 (CMT2B1) and has been described as a founder variant in t his population (De Sandre-Giovannoli 2002, Chaouch 2003, Bouhouche 2007, Ben Yao u 2007, Hamadouche 2008). Animal models of this homozygous variant are associate d with some molecular findings but not the phenotypic abnormalities seen in CMT2 B1 patients (Poitelon 2012). This variant has been identified in 6/1111132 of Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs59885338) and reported in ClinVar (Variation ID# 14498) ; however its frequency is low enough to be consistent with a recessive carrier frequency. In addition, computational prediction tools and conservation analysis suggest that the p.Arg298Cys variant may impact the protein. In summary, this v ariant meets criteria to be classified as pathogenic for CMT2B1 in an autosomal recessive manner based upon segregation studies, low frequency in controls, and functional evidence. ACMG/AMP Criteria applied: PS4; PP1_Strong; PM2_Supporting; PP3.
OMIM RCV000015590 SCV000035855 pathogenic Charcot-Marie-Tooth disease type 2B1 2007-12-01 no assertion criteria provided literature only
GeneReviews RCV000015590 SCV000087058 pathologic Charcot-Marie-Tooth disease type 2B1 2012-07-05 no assertion criteria provided curation Converted during submission to Pathogenic.
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057479 SCV000088593 not provided not provided no assertion provided not provided
GeneReviews RCV000192238 SCV000239886 pathogenic Charcot-Marie-Tooth disease 2015-04-30 no assertion criteria provided literature only

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