ClinVar Miner

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

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Total submissions: 10
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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 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

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