Submissions for variant NM_002296.4(LBR):c.1535G>A (p.Arg512Gln)

gnomAD frequency: 0.00002  dbSNP: rs754049402

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483832	SCV000574130	uncertain significance	not specified	2017-03-16	criteria provided, single submitter	clinical testing	The R512Q variant in the LBR gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R512Q variant is observed in 1/8542 (0.01%) alleles from individuals of East Asian background in the ExAC dataset. The R512Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret R512Q as a variant of uncertain significance.
Baylor Genetics	RCV001330715	SCV001522489	likely pathogenic	Regressive spondylometaphyseal dysplasia	2020-02-12	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae	RCV002526980	SCV003248742	pathogenic	not provided	2022-08-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 512 of the LBR protein (p.Arg512Gln). This variant is present in population databases (rs754049402, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of autosomal recessive LBR-related conditions (PMID: 28600779, 29068549). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 424332). 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 LBR protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987561	SCV004804213	likely pathogenic	LBR-Related Disorders	2024-01-07	criteria provided, single submitter	clinical testing	Variant summary: LBR c.1535G>A (p.Arg512Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251030 control chromosomes (gnomAD). c.1535G>A has been reported in the literature in bi-allelic individuals affected with LBR-Related Disorders (examples: Monies_2017, and Zhang_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28600779, 29068549). A different variant affecting this residue (c.1534C>T, p.R512W ) has been reported in multiple bi-allelic individuals affected with Skeletal dysplasia (PMID: 30448303, 32360156, 34467646). This data suggests that this residue may play a critical role in protein function. ClinVar contains an entry for this variant (Variation ID: 424332). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Dan Cohn Lab, University Of California Los Angeles	RCV000516056	SCV000612104	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000516056	SCV001479763	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research