rs121909490

Variant names:

• chr9-126693273-C-T
• rs121909490
• NM_001174147.2:c.691C>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.691C>T​(p.Arg231*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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: 34)
• Consequence: LMX1B NM_001174147.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.52

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 9-126693273-C-T is Pathogenic according to our data. Variant chr9-126693273-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-126693273-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.691C>T	p.Arg231*	stop_gained	Exon 4 of 8	ENST00000373474.9	NP_001167618.1
LMX1B	NM_001174146.2	c.691C>T	p.Arg231*	stop_gained	Exon 4 of 8		NP_001167617.1
LMX1B	NM_002316.4	c.691C>T	p.Arg231*	stop_gained	Exon 4 of 8		NP_002307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMX1B	ENST00000373474.9	c.691C>T	p.Arg231*	stop_gained	Exon 4 of 8	1	NM_001174147.2	ENSP00000362573.3
LMX1B	ENST00000355497.10	c.691C>T	p.Arg231*	stop_gained	Exon 4 of 8	1		ENSP00000347684.5
LMX1B	ENST00000526117.6	c.691C>T	p.Arg231*	stop_gained	Exon 4 of 8	1		ENSP00000436930.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jul 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individuals with clinical features of nail-patella syndrome (PMID: 9618165; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg231*) 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 also known as p.Arg208Ter. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 7006). -

Mar 24, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18535845, 9618165, 25898926, 33692073) -

Inborn genetic diseases Pathogenic:1

Apr 15, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.691C>T (p.R231*) alteration, located in exon 4 (coding exon 4) of the LMX1B gene, consists of a C to T substitution at nucleotide position 691. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 231. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. for nail patella syndrome; however, its clinical significance for LMX1B-related focal segmental glomerulosclerosisis is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration, referred to as "Arg208Ter", was reported in a family with nail patella syndrome (Vollrath, 1998). Based on the available evidence, this alteration is classified as pathogenic. -

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	0.60
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.89	D
Vest4		0.96
GERP RS		2.9

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: rs121909490; hg19: chr9-129455552; COSMIC: COSV105276004;