NM_021954.4:c.176C>T

Variant names:

• chr13-20143113-G-A
• rs864309691
• NM_021954.4:c.176C>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_021954.4(GJA3):​c.176C>T​(p.Pro59Leu) 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJA3 NM_021954.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.87

Genes affected

GJA3 (HGNC:4277): (gap junction protein alpha 3) The protein encoded by this gene is a connexin and is a component of lens fiber gap junctions. Defects in this gene are a cause of zonular pulverulent cataract type 3 (CZP3). [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a topological_domain Extracellular (size 30) in uniprot entity CXA3_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_021954.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 13-20143113-G-A is Pathogenic according to our data. Variant chr13-20143113-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20143113-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA3	NM_021954.4	c.176C>T	p.Pro59Leu	missense_variant	Exon 2 of 2	ENST00000241125.4	NP_068773.2
GJA3	XM_011535048.3	c.176C>T	p.Pro59Leu	missense_variant	Exon 2 of 2		XP_011533350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJA3	ENST00000241125.4	c.176C>T	p.Pro59Leu	missense_variant	Exon 2 of 2	3	NM_021954.4	ENSP00000241125.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 14 multiple types Pathogenic:4

May 09, 2024

Miami Human Genetics, University Of Miami Miller School Of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2023

Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Variant identified and curated during a GJA3 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PP1(Strong), PS4(Moderate), PM1, PM2(Supporting) PP3. The cataract phenotype/s reported for this variant are: Punctate nuclear, Pulverulent, Lamellar, and Central (Nuclear). Original variant report: PMID:15208569;19182255;21866213;25148791;27609163;26694549;34169787;36161833. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 -

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 59 of the GJA3 protein (p.Pro59Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant congenital cataracts (PMID: 15208569, 19182255, 26694549, 27609163). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217339). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GJA3 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Developmental cataract Pathogenic:2

Jan 09, 2015

Eye Genetics Research Group, Children's Medical Research Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

May 01, 2021

Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.5	M
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-9.6	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.83		Gain of catalytic residue at E62 (P = 0.0062);
MVP		0.94
MPC		2.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.98

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: rs864309691; hg19: chr13-20717252;