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.
ClinVar Genomic variation as it relates to human health
NM_001174147.2(LMX1B):c.737G>A (p.Arg246Gln)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(14)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
14
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001174147.2(LMX1B):c.737G>A (p.Arg246Gln)
Variation ID: 498798 Accession: VCV000498798.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9q33.3 9: 126693319 (GRCh38) [ NCBI UCSC ] 9: 129455598 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 2, 2018 Oct 8, 2024 Mar 14, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001174147.2:c.737G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001167618.1:p.Arg246Gln missense NM_001174146.2:c.737G>A NP_001167617.1:p.Arg246Gln missense NM_002316.4:c.737G>A NP_002307.2:p.Arg246Gln missense NC_000009.12:g.126693319G>A NC_000009.11:g.129455598G>A NG_017039.1:g.83877G>A LRG_1014:g.83877G>A LRG_1014t1:c.737G>A LRG_1014p1:p.Arg246Gln LRG_1014t2:c.737G>A LRG_1014p2:p.Arg246Gln LRG_1014t3:c.737G>A LRG_1014p3:p.Arg246Gln - Protein change
- R246Q
- Other names
- -
- Canonical SPDI
- NC_000009.12:126693318:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| LMX1B | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
593 | 634 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 6, 2023 | RCV000594256.20 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 14, 2024 | RCV001281185.13 | |
| Pathogenic/Likely pathogenic (2) |
no assertion criteria provided
|
Nov 10, 2017 | RCV001328157.10 | |
| Pathogenic (2) |
no assertion criteria provided
|
Sep 21, 2022 | RCV001807647.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 17, 2022 | RCV002476296.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 2, 2023 | RCV003994037.1 | |
|
LMX1B-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Feb 7, 2024 | RCV003915707.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 04, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000704001.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Feb 01, 2020)
|
criteria provided, single submitter
Method: research
|
Nail-patella syndrome
Affected status: yes
Allele origin:
de novo
|
Molecular Biology Laboratory, Fundació Puigvert
Study: KidneyPanel_2020
Accession: SCV001425106.1 First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021 |
|
|
|
Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Nail-patella syndrome
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058920.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Proteinuria (present)
|
|
|
Pathogenic
(Apr 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Nail-patella syndrome
Nail-patella-like renal disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002789008.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003837531.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
Comment:
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 … (more)
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) (less)
|
|
|
Pathogenic
(Nov 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001418918.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
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) … (more)
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). (less)
|
|
|
Pathogenic
(Mar 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Inherited focal segmental glomerulosclerosis
Affected status: yes
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812444.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
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), … (more)
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. (less)
|
|
|
Pathogenic
(Mar 14, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Nail-patella syndrome
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV005016556.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
|
|
|
Pathogenic
(Sep 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198678.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Apr 18, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Nephrotic syndrome
Affected status: yes
Allele origin:
unknown
|
Sydney Genome Diagnostics, Children's Hospital Westmead
Accession: SCV001449354.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Nov 10, 2017)
|
no assertion criteria provided
Method: literature only
|
Nephrotic syndrome
Affected status: yes
Allele origin:
germline
|
Yale Center for Mendelian Genomics, Yale University
Study: Yale Center for Mendelian Genomics
Accession: SCV002106769.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
|
|
|
Pathogenic
(Sep 21, 2022)
|
no assertion criteria provided
Method: literature only
|
FOCAL SEGMENTAL GLOMERULOSCLEROSIS 10
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV001449156.3
First in ClinVar: Dec 11, 2020 Last updated: Sep 24, 2022 |
Comment on evidence:
In 5 affected members of a large multigenerational family (family F) of European descent with focal segmental glomerulosclerosis-10 (FSGS10; 256020), Boyer et al. (2013) identified … (more)
In 5 affected members of a large multigenerational family (family F) of European descent with focal segmental glomerulosclerosis-10 (FSGS10; 256020), Boyer et al. (2013) identified a heterozygous c.737G-A transition in exon 4 of the LMX1B gene, resulting in an arg246-to-gln (R246Q) substitution at a highly conserved residue in the homeodomain, which is important for DNA binding and necessary for transcriptional activation. The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. The variant was not present in the Exome Sequencing Project database. Two affected members of another European family (family V) with the same phenotype were also found to carry a heterozygous R246Q mutation. Functional studies of the variant and studies of patient cells were not performed, but Boyer et al. (2013) hypothesized that the mutation might interfere with DNA binding. In a 6-year-old Japanese girl with FSGS10, Isojima et al. (2014) identified a de novo heterozygous arg246-to-gln (R246Q) substitution in the LMX1B gene. The mutation, which was found by direct sequencing of the LMX1B gene, was not present in the dbSNP database or among Japanese controls. In vitro functional expression studies showed that the mutation partially impaired transcriptional activity of LMX1B compared to controls, but not to the extent as mutations associated with NPS. There was no evidence for a dominant-negative effect, and the authors postulated haploinsufficiency. Renal biopsy from the patient showed podocyte effacement, a thickened glomerular basement membrane (GBM) due to abnormal deposition of type III collagen, and altered expression of CD2AP (604241), which plays a role in podocyte development and cytoskeleton remodeling. In 18 affected members of 2 large multigenerational families (DUK35705 and DUK34319) with FSGS10, Hall et al. (2017) identified a heterozygous R246Q mutation in the LMX1B gene. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. In vitro functional expression studies in human podocyte cell lines transfected with the mutation showed altered expression of certain key podocyte genes, suggesting that the mutation may exert a haploinsufficiency effect on the transcriptional regulation of these genes. However, additional studies indicated that the R246Q mutation exerted a dominant-negative effect on certain WT1 (607102) isoforms, which may have also caused alterations in the expression of podocyte-related genes. Hall et al. (2017) noted that the renal glomerular phenotype observed in these patients includes a wide variety of light microscopic findings, including focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, and even immune complex glomerulonephritis. Pinto e Vairo et al. (2020) identified a heterozygous c.737G-A transition (c.737G-A, NM_002316.3) in the LMX1B gene, resulting in a R246Q substitution, in a 65-year-old woman with FSGS10 and a family history of chronic kidney disease. Lei et al. (2020) identified heterozygosity for the R246Q mutation in patients from 2 families with FSGS10. (less)
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Pathogenic
(Feb 07, 2024)
|
no assertion criteria provided
Method: clinical testing
|
LMX1B-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004739470.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Nail-patella-like renal disease
Affected status: unknown
Allele origin:
paternal
|
Department of Traditional Chinese Medicine, Fujian Provincial Hospital
Accession: SCV005073708.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 |
Comment:
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 … (more)
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). (less)
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Comment:
Comment:
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)
Comment:
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).
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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).
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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)
Comment:
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).
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players. | Domingo-Gallego A | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2022 | PMID: 33532864 |
| Nail-patella-like renal disease masquerading as Fabry disease on kidney biopsy: a case report. | Pinto E Vairo F | BMC nephrology | 2020 | PMID: 32791958 |
| Myelin bodies in LMX1B-associated nephropathy: potential for misdiagnosis. | Lei L | Pediatric nephrology (Berlin, Germany) | 2020 | PMID: 32356190 |
| Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome. | Warejko JK | Clinical journal of the American Society of Nephrology : CJASN | 2018 | PMID: 29127259 |
| Dysregulation of WTI (-KTS) is Associated with the Kidney-Specific Effects of the LMX1B R246Q Mutation. | Hall G | Scientific reports | 2017 | PMID: 28059119 |
| Clinical and histological findings of autosomal dominant renal-limited disease with LMX1B mutation. | Konomoto T | Nephrology (Carlton, Vic.) | 2016 | PMID: 26560070 |
| LMX1B mutation with residual transcriptional activity as a cause of isolated glomerulopathy. | Isojima T | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2014 | PMID: 24042019 |
| LMX1B mutations cause hereditary FSGS without extrarenal involvement. | Boyer O | Journal of the American Society of Nephrology : JASN | 2013 | PMID: 23687361 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LMX1B | - | - | - | - |
| https://www.researchgate.net/publication/264162713_HETEROZYGOUS_LMX1B_MUTATION_DETECTION_IN_FAMILIAL_FSGS_WITHOUT_EXTRARENAL_MANIFESTATIONS_USING_WHOLE_EXOME_SEQUENCING | - | - | - | - |
Text-mined citations for rs1191455921 ...
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Record last updated Nov 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.