chr9-126693250-G-C

Variant names:

• chr9-126693250-G-C
• NM_001174147.2:c.668G>C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001174147.2(LMX1B):​c.668G>C​(p.Arg223Pro) 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 Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R223Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: LMX1B NM_001174147.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• 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 11 ACMG points.

• PM1: In a region_of_interest Disordered (size 53) in uniprot entity LMX1B_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001174147.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-126693250-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 9-126693250-G-C is Pathogenic according to our data. Variant chr9-126693250-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3036205.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1B	NM_001174147.2	c.668G>C	p.Arg223Pro	missense_variant	Exon 4 of 8	ENST00000373474.9	NP_001167618.1
LMX1B	NM_001174146.2	c.668G>C	p.Arg223Pro	missense_variant	Exon 4 of 8		NP_001167617.1
LMX1B	NM_002316.4	c.668G>C	p.Arg223Pro	missense_variant	Exon 4 of 8		NP_002307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMX1B	ENST00000373474.9	c.668G>C	p.Arg223Pro	missense_variant	Exon 4 of 8	1	NM_001174147.2	ENSP00000362573.3
LMX1B	ENST00000355497.10	c.668G>C	p.Arg223Pro	missense_variant	Exon 4 of 8	1		ENSP00000347684.5
LMX1B	ENST00000526117.6	c.668G>C	p.Arg223Pro	missense_variant	Exon 4 of 8	1		ENSP00000436930.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

LMX1B-related disorder Pathogenic:1

Nov 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The LMX1B c.668G>C variant is predicted to result in the amino acid substitution p.Arg223Pro. This variant was reported to occur de novo in an individual with nail-patella syndrome (Gardin et al 2020. PubMed ID: 32954044). At PreventionGenetics, we have observed this variant in a mother and child with features of nail-patella syndrome (internal data). Other variants that alter this same amino acid (p.Arg223Gln, p.Arg223Trp, p.Arg223Gly) have been reported to be pathogenic (Human Gene Mutation Database). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely 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	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;D;.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M;M;M;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.8	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		0.98
MPC		2.1
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-129455529;