rs121909489

Variant names:

• chr9-126615487-C-T
• rs121909489
• NM_001174147.2:c.244C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001174147.2(LMX1B):​c.244C>T​(p.Gln82*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LMX1B NM_001174147.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.40

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-126615487-C-T is Pathogenic according to our data. Variant chr9-126615487-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-126615487-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1B	NM_001174147.2	c.244C>T	p.Gln82*	stop_gained	Exon 2 of 8	ENST00000373474.9	NP_001167618.1
LMX1B	NM_001174146.2	c.244C>T	p.Gln82*	stop_gained	Exon 2 of 8		NP_001167617.1
LMX1B	NM_002316.4	c.244C>T	p.Gln82*	stop_gained	Exon 2 of 8		NP_002307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMX1B	ENST00000373474.9	c.244C>T	p.Gln82*	stop_gained	Exon 2 of 8	1	NM_001174147.2	ENSP00000362573.3
LMX1B	ENST00000355497.10	c.244C>T	p.Gln82*	stop_gained	Exon 2 of 8	1		ENSP00000347684.5
LMX1B	ENST00000526117.6	c.244C>T	p.Gln82*	stop_gained	Exon 2 of 8	1		ENSP00000436930.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459496 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726122

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.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 11, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Q82X variant in the LMX1B gene has been reported previously, using alternate nomenclature as Gln59Ter, in multiple affected individuals from a large family with nail patella syndrome (Vollrath et al., 1998). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q82X variant is not observed in large population cohorts (Lek et al., 2016). We interpret Q82X as a pathogenic variant. -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln82*) in the LMX1B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LMX1B are known to be pathogenic (PMID: 9590287, 15498463). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with nail-patella syndrome (PMID: 9618165). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gln59Ter. ClinVar contains an entry for this variant (Variation ID: 7005). For these reasons, this variant has been classified as Pathogenic. -

Nail-patella syndrome;C0403548:Nail-patella-like renal disease Pathogenic:1

Apr 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nail-patella syndrome Pathogenic:1

Jul 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
Vest4		0.85
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121909489; hg19: chr9-129377766;