rs121909491

Positions:

• chr9-126693250-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000373474.9(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R223P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LMX1B ENST00000373474.9 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.53

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity LMX1B_HUMAN there are 64 pathogenic changes around while only 0 benign (100%) in ENST00000373474.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-126693249-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2628831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	Protein	UniProt
LMX1B	NM_001174147.2	c.668G>A	p.Arg223Gln	missense_variant	4/8	ENST00000373474.9	NP_001167618.1
LMX1B	NM_001174146.2	c.668G>A	p.Arg223Gln	missense_variant	4/8		NP_001167617.1
LMX1B	NM_002316.4	c.668G>A	p.Arg223Gln	missense_variant	4/8		NP_002307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMX1B	ENST00000373474.9	c.668G>A	p.Arg223Gln	missense_variant	4/8	1	NM_001174147.2	ENSP00000362573	P4
LMX1B	ENST00000355497.10	c.668G>A	p.Arg223Gln	missense_variant	4/8	1		ENSP00000347684
LMX1B	ENST00000526117.6	c.668G>A	p.Arg223Gln	missense_variant	4/8	1		ENSP00000436930	A1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459266 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 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.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2023	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. Experimental studies have shown that this missense change affects LMX1B function (PMID: 9837817). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	LMX1B: PM1, PM2, PM5, PS2:Moderate, PP3, PS3:Supporting -

Nail-patella syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pediatric Nephrology Laboratory, The University of Tokyo Hospital	Mar 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -

LMX1B-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;D;.;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M;M;M;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.92	D
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	D
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

Other links and lift over

dbSNP: rs121909491; hg19: chr9-129455529; COSMIC: COSV62739259;