chr9-126693273-C-T

Position:

• chr9-126693273-C-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.Arg231Ter) 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/exons	MANE	Protein	UniProt
LMX1B	NM_001174147.2	c.691C>T	p.Arg231Ter	stop_gained	4/8	ENST00000373474.9	NP_001167618.1
LMX1B	NM_001174146.2	c.691C>T	p.Arg231Ter	stop_gained	4/8		NP_001167617.1
LMX1B	NM_002316.4	c.691C>T	p.Arg231Ter	stop_gained	4/8		NP_002307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMX1B	ENST00000373474.9	c.691C>T	p.Arg231Ter	stop_gained	4/8	1	NM_001174147.2	ENSP00000362573	P4
LMX1B	ENST00000355497.10	c.691C>T	p.Arg231Ter	stop_gained	4/8	1		ENSP00000347684
LMX1B	ENST00000526117.6	c.691C>T	p.Arg231Ter	stop_gained	4/8	1		ENSP00000436930	A1

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

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 28, 2023	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. ClinVar contains an entry for this variant (Variation ID: 7006). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2024

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1998

- -

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
MutationTaster	Benign	1.0	A;A;A;A;A
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;