Submissions for variant NM_005573.4(LMNB1):c.676C>T (p.Arg226Cys)

gnomAD frequency: 0.00032  dbSNP: rs142016804

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000791125	SCV000452352	benign	Adult-onset autosomal dominant demyelinating leukodystrophy	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000791125	SCV000930399	uncertain significance	Adult-onset autosomal dominant demyelinating leukodystrophy	2019-04-27	criteria provided, single submitter	clinical testing
Invitae	RCV001795969	SCV002126528	uncertain significance	not provided	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 226 of the LMNB1 protein (p.Arg226Cys). This variant is present in population databases (rs142016804, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with LMNB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 350615). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNB1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001795969	SCV002035433	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001795969	SCV002038312	uncertain significance	not provided		no assertion criteria provided	clinical testing