1-147908089-G-T

Position:

• 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>T​(p.Trp45Leu) 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 (★★). 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: not found (cov: 32)
• Consequence: GJA8 NM_005267.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 1-147908089-G-T is Pathogenic according to our data. 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. Variant chr1-147908089-G-T is described in Lovd as [Pathogenic]. Variant chr1-147908089-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJA8	NM_005267.5	c.134G>T	p.Trp45Leu	missense_variant	2/2	ENST00000369235.2
GJA8	XM_011509417.3	c.134G>T	p.Trp45Leu	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJA8	ENST00000369235.2	c.134G>T	p.Trp45Leu	missense_variant	2/2		NM_005267.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 1 multiple types Pathogenic:3

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(Strong), PS4(Supporting), PM1(Supporting), PM2(Supporting), PP3. Original variant report: PMID:28392901;29464339;32830442;33494148;35980487. Additional phenotype/s reported in these individual/s are: Microphthalmia and nystagmus. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene and is associated with cataract 1, multiple types (MIM#116200). While loss of function has been described for missense variants in this gene (OMIM), dominant negative is a likely mechansim because this protein forms multimers (PMID: 33218330) and variants resulting in protein truncation are prevalent in the general population (gnomAD). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Pathogenic missense variants are clustered within the connexin domain (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic, and observed in two unrelated families with cataracts. Additionally, it has been observed de novo in another individual with cataracts (ClinVar, PMID: 33494148, PMID: 29464339, PMID: 28392901). (SP) 0902 - This variant has moderate evidence for segregation with disease. This variant has segregated within a large family with cataracts, microphthalmia and nystagmus (PMID: 29464339). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 27, 2023	This missense change has been observed in individuals with autosomal dominant congenital cataracts (PMID: 28392901, 29464339). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 845873). 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. This variant disrupts the p.Trp45 amino acid residue in GJA8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18334946, 21228318, 25003127, 26694549). 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 45 of the GJA8 protein (p.Trp45Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
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	Pathogenic	0.98	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.95		Gain of glycosylation at S50 (P = 0.1702);
MVP		0.95
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.98
gMVP		0.96

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;