rs1191455921

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001174147.2(LMX1B):c.737G>A(p.Arg246Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LMX1B
NM_001174147.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 9.51

Variant links:

Genes affected

LMX1B (HGNC:6654): (LIM homeobox transcription factor 1 beta) This gene encodes a member of LIM-homeodomain family of proteins containing two N-terminal zinc-binding LIM domains, 1 homeodomain, and a C-terminal glutamine-rich domain. It functions as a transcription factor, and is essential for the normal development of dorsal limb structures, the glomerular basement membrane, the anterior segment of the eye, and dopaminergic and serotonergic neurons. Mutations in this gene are associated with nail-patella syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

LMX1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a DNA_binding_region Homeobox (size 59) in uniprot entity LMX1B_HUMAN there are 43 pathogenic changes around while only 0 benign (100%) in NM_001174147.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

PP5

Variant 9-126693319-G-A is Pathogenic according to our data. Variant chr9-126693319-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 498798.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
LMX1B	NM_001174147.2 link	c.737G>A	p.Arg246Gln	missense_variant	Exon 4 of 8	ENST00000373474.9	NP_001167618.1	O60663-1Q6ISE0
LMX1B	NM_001174146.2 link	c.737G>A	p.Arg246Gln	missense_variant	Exon 4 of 8		NP_001167617.1	B7ZLH2
LMX1B	NM_002316.4 link	c.737G>A	p.Arg246Gln	missense_variant	Exon 4 of 8		NP_002307.2	O60663-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LMX1B	ENST00000373474.9 link	c.737G>A	p.Arg246Gln	missense_variant	Exon 4 of 8	1	NM_001174147.2	ENSP00000362573.3	O60663-1
LMX1B	ENST00000355497.10 link	c.737G>A	p.Arg246Gln	missense_variant	Exon 4 of 8	1		ENSP00000347684.5	O60663-3
LMX1B	ENST00000526117.6 link	c.737G>A	p.Arg246Gln	missense_variant	Exon 4 of 8	1		ENSP00000436930.1	O60663-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1444634

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717430

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Jan 04, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LMX1B function (PMID: 24042019, 28059119). This missense change has been observed in individuals with focal segmental glomerulosclerosis (PMID: 23687361, 26560070, 28059119). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 246 of the LMX1B protein (p.Arg246Gln). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 498798). 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 LMX1B protein function. -

Sep 06, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate this variant partially impairs transcriptional activity, indicating haploinsufficiency (Isojima et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26560070, 28059119, 31328266, 24042019, 32791958, 33725694, 32356190, 32774956, 23891399, 28844315, 29246420, 28780565, 27450397, 30295827, 30647093, 29127259, 23687361, 28204945) -

Nail-patella syndrome

Pathogenic:3

Feb 01, 2020

Molecular Biology Laboratory, Fundació Puigvert

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000498798, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (, PS3_S). A different missense change at the same codon has been reported to be associated with LMX1B related disorder (ClinVar ID: VCV000812901, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.908, 3CNET: 0.933, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Nail-patella-like renal disease

Pathogenic:2

Sep 21, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Department of Traditional Chinese Medicine, Fujian Provincial Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

We identified the LMX1B mutation in a young man with nephrotic syndrome who had no clinical symptoms other than renal, and the mutation site was found to be pathogenic according to the ACMG guidelines as it corresponded to PS3 (Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product)+PS4_Supporting (The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls)+PM2 (Absent from controls in Exome Sequencing Project, 1000 Genomes or ExAC)+PP1_Strong (Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease)+PP3 (Multiple lines of computational evidence support a deleterious effect on the gene or gene product). -

Nephrotic syndrome

Pathogenic:2

Apr 18, 2014

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This individual is heterozygous for a known pathogenic variant, c.737G>A p.(Arg246Gln) in the LMX1B gene. This variant is located in the homeobox domain of the LMX1B gene and occurs in a highly conserved amino acid residue. Originally described in a patient with nail patella syndrome (NPS) (OMIM# 602575); however, more recent reports have described this variant in multiple families with glomerular pathologies, including isolated FSGS, Nail-Patella-like Renal Disease (NPLRD) and Steroid resistant nephrotic syndrome (Boyer et al, J Am Soc Nephrol 24 (2013): 1216-1222; Hall et al, Sci Rep (2017) 7:39933). This variant is considered to be pathogenic according to the ACMG guidelines. -

Nov 10, 2017

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

LMX1B-related disorder

Pathogenic:1

Feb 07, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The LMX1B c.737G>A variant is predicted to result in the amino acid substitution p.Arg246Gln. This variant has been repeatedly reported to be causative for LMX1B-related glomerulopathy (see for example, reported as de novo at Supplementary Table 2 of Domingo-Gallego et al. 2021. PubMed ID: 33532864; Boyer et al. 2013. PubMed ID: 23687361; Isojima et al. 2014. PubMed ID: 24042019; Konomoto et al. 2016. PubMed ID: 26560070; Hall et al. 2017. PubMed ID: 28059119). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Nail-patella syndrome;C0403548:Nail-patella-like renal disease

Pathogenic:1

Mar 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inherited focal segmental glomerulosclerosis

Pathogenic:1

Mar 02, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in LMX1B is predicted to replace arginine with glutamine at codon 246, p.(Arg246Gln). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the homeobox domain. There is a small physicochemical difference between arginine and glutamine. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in probands/families with focal segmental glomerulosclerosis without extrarenal involvement or unspecified glomerulopathy, including at least one individual where the variant was identified as a de novo occurrence with unconfirmed parental relationships. It also segregates with kidney disease in multiple families (PMID: 23687361, 24042019, 28059119, 32791958, 32356190, 33532864). In vitro assays of LMX1B transcriptional activity in mammalian cell lines showed partially impaired transcriptional activity suggesting the variant may have dominant negative and haploinsufficiency effects (PMID: 24042019, 28059119). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PS4_Moderate, PM6, PS3_Supporting, PM2_Supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

.;D;.;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.9

L;L;L;.

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.9

D;D;D;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;.;.;D

Vest4

0.86

MutPred

0.77

.;.;.;Gain of ubiquitination at K220 (P = 0.028);

MVP

0.95

MPC

1.8

ClinPred

1.0

GERP RS

5.0

Varity_R

0.84

gMVP

0.90

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over