rs573510559

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_002296.4(LBR):c.1757G>A(p.Arg586His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R586C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

LBR
NM_002296.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4U:1

Conservation

PhyloP100: 7.78

Publications

10 publications found

Variant links:

Genes affected

LBR (HGNC:6518): (lamin B receptor) The protein encoded by this gene belongs to the ERG4/ERG24 family. It localized in the nuclear envelope inner membrane and anchors the lamina and the heterochromatin to the membrane. It may mediate interaction between chromatin and lamin B. Mutations of this gene has been associated with autosomal recessive HEM/Greenberg skeletal dysplasia. Alternative splicing occurs at this locus and two transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

LBR Gene-Disease associations (from GenCC):

Greenberg dysplasia
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P
Pelger-Huet anomaly
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
regressive spondylometaphyseal dysplasia
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

LBR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_002296.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-225403395-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1320971.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 1-225403394-C-T is Pathogenic according to our data. Variant chr1-225403394-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 545626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LBR	NM_002296.4 link	c.1757G>A	p.Arg586His	missense_variant	Exon 14 of 14	ENST00000272163.9	NP_002287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LBR	ENST00000272163.9 link	c.1757G>A	p.Arg586His	missense_variant	Exon 14 of 14	1	NM_002296.4	ENSP00000272163.4

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151464

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000358

AC:

AN:

251460

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461506

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33466

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000202

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111706

Other (OTH)

AF:

0.0000331

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000264

AC:

AN:

151582

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

73964

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41336

American (AMR)

AF:

0.00

AC:

AN:

15208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.000194

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67910

Other (OTH)

AF:

0.00

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000543

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pelger-Huët anomaly;C0748397:Reynolds syndrome;C2931048:Greenberg dysplasia;C4747922:Regressive spondylometaphyseal dysplasia

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PP3_Moderate+PM3_VeryStrong+PP4 -

Regressive spondylometaphyseal dysplasia

Pathogenic:1

Feb 03, 2022

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Feb 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 586 of the LBR protein (p.Arg586His). This variant is present in population databases (rs573510559, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive LBR-related conditions (PMID: 23824842, 34567078, 36307859). 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: 545626). 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 with a positive predictive value of 80%. This variant disrupts the p.Arg586 amino acid residue in LBR. Other variant(s) that disrupt this residue have been observed in individuals with LBR-related conditions (PMID: 30448303), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Greenberg dysplasia

Pathogenic:1

Aug 28, 2022

Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pelger-Huët anomaly

Uncertain:1

Mar 19, 2021

New York Genome Center

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

4.3

H;H

PhyloP100

7.8

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-4.4

D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.89

MutPred

0.93

Loss of stability (P = 0.0332);Loss of stability (P = 0.0332);

MVP

0.93

MPC

0.57

ClinPred

1.0

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.82

gMVP

0.91

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over