rs864309688

Positions:

• chr1-147908089-G-C
• chr1-147908089-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_005267.5(GJA8):​c.134G>C​(p.Trp45Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,168 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W45R) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: GJA8 NM_005267.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.07

Genes affected

GJA8 (HGNC:4281): (gap junction protein alpha 8) This gene encodes a transmembrane connexin protein that is necessary for lens growth and maturation of lens fiber cells. The encoded protein is a component of gap junction channels and functions in a calcium and pH-dependent manner. Mutations in this gene have been associated with zonular pulverulent cataracts, nuclear progressive cataracts, and cataract-microcornea syndrome. [provided by RefSeq, Dec 2009]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_005267.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-147908089-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 845873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 1-147908089-G-C is Pathogenic according to our data. Variant chr1-147908089-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-147908089-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJA8	NM_005267.5	c.134G>C	p.Trp45Ser	missense_variant	2/2	ENST00000369235.2
GJA8	XM_011509417.3	c.134G>C	p.Trp45Ser	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJA8	ENST00000369235.2	c.134G>C	p.Trp45Ser	missense_variant	2/2		NM_005267.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 1 multiple types Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GJA8-related disorder (ClinVar ID: VCV000217335 / PMID: 18334946). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26694549). Different missense changes at the same codon (p.Trp45Arg, p.Trp45Leu) have been reported to be associated with GJA8-related disorder (ClinVar ID: VCV000845873 / PMID: 28392901 , 30498267). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 06, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJA8 function (PMID: 21228318, 25003127). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJA8 protein function. ClinVar contains an entry for this variant (Variation ID: 217335). This missense change has been observed in individual(s) with bilateral congenital cataracts (PMID: 18334946, 26694549). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 45 of the GJA8 protein (p.Trp45Ser). -
Likely pathogenic, criteria provided, single submitter	curation	Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania	Jan 21, 2023	Variant identified and curated during a GJA8 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PP1(Moderate), PM1(Supporting), PS4(Supporting), PM2(Supporting), PM5(Supporting), PP3. Original variant report: PMID:18334946;26694549;28839118;30076350. The cataract phenotype/s reported for this variant are: Jellyfish-like, and Anterior cortical/nuclear. Additional phenotype/s reported in these individual/s are: latent nystagmus. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 -

Developmental cataract Pathogenic:2

Pathogenic, no assertion criteria provided	research	Eye Genetics Research Group, Children's Medical Research Institute	Jan 09, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Ophthalmology, Flinders University	Jul 29, 2016	- -

GJA8-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2024

The GJA8 c.134G>C variant is predicted to result in the amino acid substitution p.Trp45Ser. This variant has been reported to segregate with disease in a kindred with congenital cataracts and microcornea (Vanita et al. 2008. PubMed ID: 18334946). This variant has been reported in additional, unrelated individuals with congenital cataracts (Javadiyan et al. 2017. PubMed ID: 28839118; Ma et al. 2016. PubMed ID: 26694549; Zamani et al. 2022. PubMed ID: 35754085). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-14	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.96		Gain of disorder (P = 1e-04);
MVP		0.95
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.96
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs864309688; hg19: chr1-147380216;