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

Total submissions: 10

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	2020-10-19	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 founder mutation in North African countries and it has been reported to segregate with autosomal recessive Charcot-Marie-Tooth disease in several affected families (PMID: 18549403, 14607793, 17347251). Heterozygous carriers have been reported to be clinically unaffected (PMID: 11799477). 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.
Mendelics	RCV000986429	SCV001135429	pathogenic	Hutchinson-Gilford syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000057479	SCV001248555	pathogenic	not provided	2017-05-01	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV001176301	SCV001340218	uncertain significance	Cardiomyopathy	2020-11-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 298 of the LMNA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant is a well-known founder mutation in North African countries and has been reported to segregate with autosomal recessive Charcot-Marie-Tooth type 2 in affected families (PMID: 18549403, 14607793, 17347251; Clinvar variation ID: 14498). This variant has been identified in 9/250398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant has not yet been reported in individuals affected with cardiovascular disorders in the literature, and the available evidence is insufficient to determine the role of this variant in autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
OMIM	RCV000015590	SCV000035855	pathogenic	Charcot-Marie-Tooth disease type 2B1	2007-12-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057479	SCV000088593	not provided	not provided		no assertion provided	not provided
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000057479	SCV001800542	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics,Academic Medical Center	RCV000057479	SCV001925058	pathogenic	not provided		no assertion criteria provided	clinical testing