rs1191455921
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_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. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R246P) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
LMX1B
NM_001174147.2 missense
NM_001174147.2 missense
Scores
15
1
2
Clinical Significance
Conservation
PhyloP100: 9.51
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]
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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 63 pathogenic changes around while only 0 benign (100%) in NM_001174147.2
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr9-126693319-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 812901.Status of the report is no_assertion_criteria_provided, 0 stars.
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMX1B | NM_001174147.2 | c.737G>A | p.Arg246Gln | missense_variant | 4/8 | ENST00000373474.9 | |
LMX1B | NM_001174146.2 | c.737G>A | p.Arg246Gln | missense_variant | 4/8 | ||
LMX1B | NM_002316.4 | c.737G>A | p.Arg246Gln | missense_variant | 4/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMX1B | ENST00000373474.9 | c.737G>A | p.Arg246Gln | missense_variant | 4/8 | 1 | NM_001174147.2 | P4 | |
LMX1B | ENST00000355497.10 | c.737G>A | p.Arg246Gln | missense_variant | 4/8 | 1 | |||
LMX1B | ENST00000526117.6 | c.737G>A | p.Arg246Gln | missense_variant | 4/8 | 1 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1444634Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 717430
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
AC:
0
AN:
1444634
Hom.:
Cov.:
34
AF XY:
AC XY:
0
AN XY:
717430
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 23, 2023 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 04, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2022 | 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. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LMX1B function (PMID: 24042019, 28059119). ClinVar contains an entry for this variant (Variation ID: 498798). 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 variant is not present in population databases (gnomAD no frequency). 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). - |
Nail-patella syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | research | Molecular Biology Laboratory, Fundació Puigvert | Feb 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 14, 2024 | - - |
Nephrotic syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Sydney Genome Diagnostics, Children's Hospital Westmead | Apr 18, 2014 | 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. - |
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Nov 10, 2017 | - - |
LMX1B-related condition Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 07, 2024 | 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-like renal disease Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 21, 2022 | - - |
Nail-patella syndrome;C0403548:Nail-patella-like renal disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 17, 2022 | - - |
Inherited focal segmental glomerulosclerosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 02, 2023 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;L;L;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
1.0
.;.;.;D
Vest4
MutPred
0.77
.;.;.;Gain of ubiquitination at K220 (P = 0.028);
MVP
MPC
1.8
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at