NM_001161748.2:c.388C>T

Variant names:

• chr19-51380577-G-A
• rs1568480054
• NM_001161748.2:c.388C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001161748.2(LIM2):​c.388C>T​(p.Arg130Cys) variant causes a missense 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LIM2 NM_001161748.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.97

Genes affected

LIM2 (HGNC:6610): (lens intrinsic membrane protein 2) This gene encodes an eye lens-specific protein found at the junctions of lens fiber cells, where it may contribute to cell junctional organization. It acts as a receptor for calmodulin, and may play an important role in both lens development and cataractogenesis. Mutations in this gene have been associated with cataract formation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 19-51380577-G-A is Pathogenic according to our data. Variant chr19-51380577-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 625113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-51380577-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIM2	NM_001161748.2	c.388C>T	p.Arg130Cys	missense_variant	Exon 4 of 5	ENST00000596399.2	NP_001155220.1
LIM2	NM_030657.4	c.514C>T	p.Arg172Cys	missense_variant	Exon 4 of 5		NP_085915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIM2	ENST00000596399.2	c.388C>T	p.Arg130Cys	missense_variant	Exon 4 of 5	1	NM_001161748.2	ENSP00000472090.2
LIM2	ENST00000221973.7	c.514C>T	p.Arg172Cys	missense_variant	Exon 4 of 5	1		ENSP00000221973.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461884 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 727240

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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 19 multiple types Pathogenic:4

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 172 of the LIM2 protein (p.Arg172Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant congenital cataracts (PMID: 32202185, 33078099). It has also been observed to segregate with disease in related individuals. This variant is also known as c.388C>T (p.R130C). ClinVar contains an entry for this variant (Variation ID: 625113). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Jul 05, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 22, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cataract Pathogenic:1

Nov 16, 2017

Department of Ophthalmology, Fourth Military Medical University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

In this work, we identified a novel LIM2 mutation associated with autosomal dominant congenital membranous cataracts, which was known to be inherited by autosomal recessive pattern in all reported families with LIM2-mutant related cataract. Besides, morphological changes of the lens were characterized by macroscopically thin lenses, elongated axial length and microcosmically immature fiber cells which existed in the lens nucleus. Thus, we firstly suggest the impact of LIM2 during lens fiber cells differentiation, which could extend the understanding of the gene itself and give insight of the relationship between lens fiber cells differentiation and membranous cataract. All above are new finding and new concepts. -

LIM2-related disorder Pathogenic:1

Jan 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The LIM2 c.514C>T variant is predicted to result in the amino acid substitution p.Arg172Cys. This variant was reported as a recurrent variant in multiple individuals with autosomal dominant cataract (reported as p.Arg130Cys in the literature, Berry et al 2020. PubMed ID: 32202185; Pei et al 2020. PubMed ID: 33078099; Wang et al 2021. PubMed ID: 33708862; Berry et al 2022. PubMed ID: 35736209; Fernández-Alcalde et al 2021. PubMed ID: 33923544). 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 pathogenic. -

not provided Pathogenic:1

Apr 06, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28450710, 33708862, 33923544, 33078099, 32202185, 27535533) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	.;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Uncertain	2.3	.;M
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.1	D;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.70
MutPred		0.84		.;Loss of MoRF binding (P = 0.0303);
MVP		0.98
MPC		0.57
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.56
gMVP		0.83

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: rs1568480054; hg19: chr19-51883831;