rs121909491

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.668G>A(p.Arg223Gln) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 34)

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:8

Conservation

PhyloP100: 9.53

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a region_of_interest Disordered (size 53) in uniprot entity LMX1B_HUMAN there are 7 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, 0.948

PP5

Variant 9-126693250-G-A is Pathogenic according to our data. Variant chr9-126693250-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-126693250-G-A is described in Lovd as [Pathogenic]. Variant chr9-126693250-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1B	NM_001174147.2 link	c.668G>A	p.Arg223Gln	missense_variant	Exon 4 of 8	ENST00000373474.9	NP_001167618.1	O60663-1Q6ISE0
LMX1B	NM_001174146.2 link	c.668G>A	p.Arg223Gln	missense_variant	Exon 4 of 8		NP_001167617.1	B7ZLH2
LMX1B	NM_002316.4 link	c.668G>A	p.Arg223Gln	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.668G>A	p.Arg223Gln	missense_variant	Exon 4 of 8	1	NM_001174147.2	ENSP00000362573.3	O60663-1
LMX1B	ENST00000355497.10 link	c.668G>A	p.Arg223Gln	missense_variant	Exon 4 of 8	1		ENSP00000347684.5	O60663-3
LMX1B	ENST00000526117.6 link	c.668G>A	p.Arg223Gln	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

AF:

0.00

AC:

AN:

1459266

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725750

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LMX1B: PM1, PM2, PM5, PS2:Moderate, PP3, PS3:Supporting -

Mar 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 223 of the LMX1B protein (p.Arg223Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with LMX1B-related conditions (PMID: 9837817, 28780565, 29869118). In at least one individual the variant was observed to be de novo. This variant is also known as c.599G>A, p.Arg200Gln. ClinVar contains an entry for this variant (Variation ID: 7007). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LMX1B function (PMID: 9837817). For these reasons, this variant has been classified as Pathogenic. -

May 10, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9837817, 25898926, 29869118, 28780565, 30647093, 32457516, 32604935) -

Nail-patella syndrome

Pathogenic:3

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2020

Pediatric Nephrology Laboratory, The University of Tokyo Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

LMX1B-related disorder

Pathogenic:1

Jun 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The LMX1B c.668G>A variant is predicted to result in the amino acid substitution p.Arg223Gln. This variant has been reported in multiple unrelated families to be pathogenic for nail-patella syndrome (reported as R200Q/G599A in McIntosh et al. 1998. PubMed ID: 9837817; Bezdíčka et al. 2018. PubMed ID: 29869118; Sen et al. 2017. PubMed ID: 28780565). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

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

Pathogenic:1

Jun 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

.;D;.;D

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.4

M;M;M;.

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-3.9

D;D;D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;.;.;D

Vest4

0.96

MVP

0.99

MPC

1.9

ClinPred

1.0

GERP RS

5.0

Varity_R

0.93

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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