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

Total submissions: 7

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