VCV002581012.5 - ClinVar

NM_005267.5(GJA8):c.592C>T (p.Arg198Trp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(3); Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005267.5(GJA8):c.592C>T (p.Arg198Trp)

Variation ID: 2581012 Accession: VCV002581012.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q21.2 1: 147908547 (GRCh38) [ NCBI UCSC ] 1: 147380674 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Sep 30, 2023	Nov 24, 2024	Feb 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005267.5:c.592C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005258.2:p.Arg198Trp	missense
NM_005267.4:c.592C>T
NC_000001.11:g.147908547C>T
NC_000001.10:g.147380674C>T
NG_016242.1:g.10729C>T
NG_016242.2:g.10754C>T

... more HGVS ... less HGVS

Protein change

R198W

Other names

Canonical SPDI

NC_000001.11:147908546:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GJA8		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	244	533

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cataract 1 multiple types	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jan 21, 2023	RCV003330247.6
Microphthalmia, isolated, with cataract 1	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2023	RCV004786920.1
not provided	Pathogenic (1)	criteria provided, single submitter	Feb 26, 2024	RCV004719321.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Sep 25, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cataract 1 multiple types Affected status: yes Allele origin: unknown	Dr. med. U. Finckh, Human Genetics, Eurofins MVZ Accession: SCV004037274.1 First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 Comment: Heterozygous in a proband with isolated congenital bilateral cataract. The variant is not present in population databases (gnomAD). Another missense change of this codon has … (more) Heterozygous in a proband with isolated congenital bilateral cataract. The variant is not present in population databases (gnomAD). Another missense change of this codon has already been described as pathogenic. Residual uncertainty remains as there were no parental samples available for testing. (less)
Pathogenic (Nov 04, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cataract 1 multiple types Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004291991.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 16604058‚ 24281366‚ 20806042 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg198 amino acid residue in GJA8. Other variant(s) that disrupt this … (more) For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg198 amino acid residue in GJA8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16604058, 24281366; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individuals with autosomal dominant congenital cataract (PMID: 20806042; Invitae). 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 arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 198 of the GJA8 protein (p.Arg198Trp). (less)
Uncertain significance (Jan 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Cataract 1 multiple types Affected status: yes Allele origin: germline	Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania Accession: SCV005081760.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (2) PubMed: 20806042‚ 33923544 Comment: 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), PM2(Supporting), PP3. … (more) 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), PM2(Supporting), PP3. Original variant report: PMID:20806042;33923544. The cataract phenotype reported for this variant is: Nuclear. Additional phenotype/s reported in these individual/s are: Microcornea, and Microphthalmia. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 (less)
Pathogenic (Oct 31, 2023)	criteria provided, single submitter (ACMG/ClinGen CNV Guidelines, 2019) Method: clinical testing	Microphthalmia, isolated, with cataract 1 Affected status: yes Allele origin: inherited	Molecular Genetics of Human Eye Development, Oxford Brookes University Accession: SCV005044866.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (1) PubMed: 20806042 Number of individuals with the variant: 3 Sex: mixed
Pathogenic (Feb 26, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005325209.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated … (more) Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27785597, 23300808, 27990357, 23592913, 25003127, 33816482, 36729443, 20806042) (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg198 amino acid residue in GJA8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16604058, 24281366; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individuals with autosomal dominant congenital cataract (PMID: 20806042; Invitae). 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 arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 198 of the GJA8 protein (p.Arg198Trp).

Comment:

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), PM2(Supporting), PP3. Original variant report: PMID:20806042;33923544. The cataract phenotype reported for this variant is: Nuclear. Additional phenotype/s reported in these individual/s are: Microcornea, and Microphthalmia. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320

Comment:

Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27785597, 23300808, 27990357, 23592913, 25003127, 33816482, 36729443, 20806042)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular and Genetic Mechanism of Non-Syndromic Congenital Cataracts. Mutation Screening in Spanish Families.	Fernández-Alcalde C	Genes	2021	PMID: 33923544
Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1.	Prokudin I	European journal of human genetics : EJHG	2014	PMID: 24281366
A novel mutation in GJA8 causing congenital cataract-microcornea syndrome in a Chinese pedigree.	Hu S	Molecular vision	2010	PMID: 20806042
Novel mutations in GJA8 associated with autosomal dominant congenital cataract and microcornea.	Devi RR	Molecular vision	2006	PMID: 16604058

Text-mined citations for this variant ...

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_005267.5(GJA8):c.592C>T (p.Arg198Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...