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NM_001174147.2(LMX1B):c.737G>A (p.Arg246Gln) AND Inherited focal segmental glomerulosclerosis

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 2, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003994037.1

Allele description [Variation Report for NM_001174147.2(LMX1B):c.737G>A (p.Arg246Gln)]

NM_001174147.2(LMX1B):c.737G>A (p.Arg246Gln)

Gene:
LMX1B:LIM homeobox transcription factor 1 beta [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
9q33.3
Genomic location:
Preferred name:
NM_001174147.2(LMX1B):c.737G>A (p.Arg246Gln)
HGVS:
  • NC_000009.12:g.126693319G>A
  • NG_017039.1:g.83877G>A
  • NM_001174146.2:c.737G>A
  • NM_001174147.2:c.737G>AMANE SELECT
  • NM_002316.4:c.737G>A
  • NP_001167617.1:p.Arg246Gln
  • NP_001167617.1:p.Arg246Gln
  • NP_001167618.1:p.Arg246Gln
  • NP_002307.2:p.Arg246Gln
  • NP_002307.2:p.Arg246Gln
  • LRG_1014t1:c.737G>A
  • LRG_1014t2:c.737G>A
  • LRG_1014t3:c.737G>A
  • LRG_1014:g.83877G>A
  • LRG_1014p1:p.Arg246Gln
  • LRG_1014p2:p.Arg246Gln
  • LRG_1014p3:p.Arg246Gln
  • NC_000009.11:g.129455598G>A
  • NM_001174146.1:c.737G>A
  • NM_001174147.2:c.737G>A
  • NM_002316.3:c.737G>A
  • NM_002316.4:c.737G>A
Protein change:
R246Q; ARG246GLN
Links:
OMIM: 602575.0014; dbSNP: rs1191455921
NCBI 1000 Genomes Browser:
rs1191455921
Molecular consequence:
  • NM_001174146.2:c.737G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001174147.2:c.737G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002316.4:c.737G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Inherited focal segmental glomerulosclerosis
Identifiers:
MONDO: MONDO:0005363; MedGen: CN327126; OMIM: PS603278

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004812444Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Mar 2, 2023) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

LMX1B mutations cause hereditary FSGS without extrarenal involvement.

Boyer O, Woerner S, Yang F, Oakeley EJ, Linghu B, Gribouval O, Tête MJ, Duca JS, Klickstein L, Damask AJ, Szustakowski JD, Heibel F, Matignon M, Baudouin V, Chantrel F, Champigneulle J, Martin L, Nitschké P, Gubler MC, Johnson KJ, Chibout SD, Antignac C.

J Am Soc Nephrol. 2013 Jul;24(8):1216-22. doi: 10.1681/ASN.2013020171. Epub 2013 May 16.

PubMed [citation]
PMID:
23687361
PMCID:
PMC3736714

LMX1B mutation with residual transcriptional activity as a cause of isolated glomerulopathy.

Isojima T, Harita Y, Furuyama M, Sugawara N, Ishizuka K, Horita S, Kajiho Y, Miura K, Igarashi T, Hattori M, Kitanaka S.

Nephrol Dial Transplant. 2014 Jan;29(1):81-8. doi: 10.1093/ndt/gft359. Epub 2013 Sep 15.

PubMed [citation]
PMID:
24042019
See all PubMed Citations (7)

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV004812444.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 12, 2024