1-147908106-G-A

Variant names:

• chr1-147908106-G-A
• rs864309703
• NM_005267.5:c.151G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3 PP5

The NM_005267.5(GJA8):​c.151G>A​(p.Asp51Asn) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D51E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA8 NM_005267.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 8.07
• Publications: 10 publications found

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]

GJA8 Gene-Disease associations (from GenCC):

• cataract 1 multiple types

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• cataract - microcornea syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset sutural cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulverulent cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr1-147908108-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 574353.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 49 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Trascript score misZ: -0.35816 (below the threshold of 3.09). GenCC associations: The gene is linked to cataract 1 multiple types, cataract - microcornea syndrome, early-onset nuclear cataract, early-onset sutural cataract, pulverulent cataract, total early-onset cataract.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839
• PP5: Variant 1-147908106-G-A is Pathogenic according to our data. Variant chr1-147908106-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217355.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005267.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA8	NM_005267.5	MANE Select	c.151G>A	p.Asp51Asn	missense	Exon 2 of 2	NP_005258.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA8	ENST00000369235.2	TSL:6 MANE Select	c.151G>A	p.Asp51Asn	missense	Exon 2 of 2	ENSP00000358238.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cataract 1 multiple types Pathogenic:3 Uncertain:1

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been previously reported as de novo in a similarly affected individual (PMID: 26694549, PS2_S) A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000521485,VCV000574353, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.787, PP3_P). A missense variant is a common mechanism associated with Cataract 1 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Jan 21, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Variant identified and curated during a GJA8 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PS4(Supporting), PM1(Supporting), PM2(Supporting), PM6(Supporting), PP3. Original variant report: PMID:26694549;29464339. Additional phenotype/s reported in these individual/s are: Microphthalmia, unilateral sclerocornea. Microphthalmia, anterior segment dysgenesis, persistent pupillary membrane. Microphthalmia, deep set eyes, corneal leukoma, buphthalmos, corectopia, nystagmus. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320

May 10, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 51 of the GJA8 protein (p.Asp51Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant cataract (PMID: 26694549, 29464339). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 217355). 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 with a positive predictive value of 80%. This variant disrupts the p.Asp51 amino acid residue in GJA8. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

acorea-microphthalmia-cataract syndrome Pathogenic:1

Jul 07, 2023

UOEH Ophthalmology lab, University Of Occupational And Environmental Health, Japan

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

It provides a new screening target for prenatal diagnosis of familial acorea.

Developmental cataract Pathogenic:1

Jan 09, 2015

Eye Genetics Research Group, Children's Medical Research Institute

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		8.1
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.62		Gain of glycosylation at S50 (P = 0.1682)
MVP		0.96
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.44
gMVP		0.95
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs864309703; hg19: chr1-147380233; COSMIC: COSV53791343;