VCV000500507.29 - ClinVar

NM_172337.2(OTX2):c.402dup (p.Ser135Leufs)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_172337.2(OTX2):c.402dup (p.Ser135Leufs)

Variation ID: 500507 Accession: VCV000500507.29

Type and length

Duplication, 1 bp

Location

Cytogenetic: 14q22.3 14: 56802202-56802203 (GRCh38) [ NCBI UCSC ] 14: 57268920-57268921 (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	Apr 4, 2013	Dec 22, 2024	Sep 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_021728.4:c.426dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_068374.1:p.Ser143fs	frameshift
NM_001270523.2:c.402dup	NP_001257452.1:p.Ser135fs	frameshift
NM_001270524.2:c.402dup	NP_001257453.1:p.Ser135fs	frameshift
NM_001270525.2:c.426dup	NP_001257454.1:p.Ser143fs	frameshift
NM_172337.3:c.402dup	NP_758840.1:p.Ser135fs	frameshift
NR_073034.2:n.537dup		non-coding transcript variant
NR_073036.2:n.461dup		non-coding transcript variant
NC_000014.9:g.56802208dup
NC_000014.8:g.57268926dup
NG_008204.1:g.13264dup
LRG_718t1:c.426dup	LRG_718p1:p.Ser143fs

... more HGVS ... less HGVS

Protein change

S135fs, S143fs

Other names

Canonical SPDI

NC_000014.9:56802202:GGGGGG:GGGGGGG

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

dbSNP: rs1555350223 ClinGen: CA658798215 OMIM: 600037.0005 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.
OTX2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	259	275

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.
Syndromic microphthalmia type 5	Pathogenic (2)	criteria provided, single submitter	Mar 31, 2022	RCV000594111.5
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 1, 2023	RCV000596696.26
Anophthalmia-microphthalmia syndrome	Pathogenic (1)	criteria provided, single submitter	Aug 2, 2023	RCV003530088.2

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.
Pathogenic (Mar 28, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000706499.2 First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=OTX2 Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed
Pathogenic (Mar 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Syndromic microphthalmia type 5 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002768004.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (2) PubMed: 18628516‚ 30268123 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with syndromic microphthalmia 5 (MIM#610125). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 30268123). (I) 0115 - Variants in this gene are known to have variable expressivity. A wide range of inter- and intrafamilial phenotypic variability has been reported (PMID: 30268123). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is predicted to lose the transactivation domain (PMID: 18628516). (I) 0701 - Other variants predicted to result in a truncated protein comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported as de novo in a patient with anophthalmia, short stature, and partial growth hormone deficiency (PMID: 18628516) and has also been reported as pathogenic in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that the mutant protein barely retained transactivation activities (PMID: 18628516). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Aug 02, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Anophthalmia-microphthalmia syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004297099.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 18628516 Comment: ClinVar contains an entry for this variant (Variation ID: 500507). This variant is also known as p.L135fsX136. This premature translational stop signal has been observed … (more) ClinVar contains an entry for this variant (Variation ID: 500507). This variant is also known as p.L135fsX136. This premature translational stop signal has been observed in individual(s) with OTX2-related conditions (PMID: 18628516). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser135Leufs*2) in the OTX2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 155 amino acid(s) of the OTX2 protein. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects OTX2 function (PMID: 18628516). (less)
Pathogenic (Sep 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001961438.21 First in ClinVar: Oct 08, 2021 Last updated: Dec 22, 2024	Comment: OTX2: PVS1:Strong, PM2, PS4:Moderate, PM6:Supporting, PS3:Supporting Number of individuals with the variant: 2
Pathogenic (Oct 01, 2008)	no assertion criteria provided Method: literature only	MICROPHTHALMIA, SYNDROMIC 5 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000044213.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 18628516 Comment on evidence: In an 8.5-year-old Japanese girl with bilateral clinical anophthalmia, short stature, developmental delay, and partial growth hormone deficiency (MCOPS5; 610125), Dateki et al. (2008) identified … (more) In an 8.5-year-old Japanese girl with bilateral clinical anophthalmia, short stature, developmental delay, and partial growth hormone deficiency (MCOPS5; 610125), Dateki et al. (2008) identified heterozygosity for a de novo 1-bp insertion (402insC) in exon 5 of the OTX2 gene, predicted to cause a frameshift and premature termination codon resulting in retention of the homeodomain but loss of the transactivation domain as well as the SIWSPA motif. The mutation was not found in either parent. Functional studies showed that both wildtype and mutant protein localized to the nucleus; however, wildtype OTX2 markedly transactivated the reporters for the IRBP (180290), HESX1 (601802), and POU1F1 (173110) genes, whereas mutant OTX2 barely retained transactivation activities and had no dominant-negative effects. (less)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with syndromic microphthalmia 5 (MIM#610125). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 30268123). (I) 0115 - Variants in this gene are known to have variable expressivity. A wide range of inter- and intrafamilial phenotypic variability has been reported (PMID: 30268123). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is predicted to lose the transactivation domain (PMID: 18628516). (I) 0701 - Other variants predicted to result in a truncated protein comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported as de novo in a patient with anophthalmia, short stature, and partial growth hormone deficiency (PMID: 18628516) and has also been reported as pathogenic in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that the mutant protein barely retained transactivation activities (PMID: 18628516). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

ClinVar contains an entry for this variant (Variation ID: 500507). This variant is also known as p.L135fsX136. This premature translational stop signal has been observed in individual(s) with OTX2-related conditions (PMID: 18628516). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser135Leufs*2) in the OTX2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 155 amino acid(s) of the OTX2 protein. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects OTX2 function (PMID: 18628516).

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
New insights into the phenotypic spectrum of 14q22q23 deletions: a case report and literature review.	Pichiecchio A	BMC medical genomics	2018	PMID: 30268123
OTX2 mutation in a patient with anophthalmia, short stature, and partial growth hormone deficiency: functional studies using the IRBP, HESX1, and POU1F1 promoters.	Dateki S	The Journal of clinical endocrinology and metabolism	2008	PMID: 18628516
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=OTX2	-	-	-	-

Text-mined citations for rs1555350223 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 22, 2024

ClinVar Genomic variation as it relates to human health

NM_172337.2(OTX2):c.402dup (p.Ser135Leufs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1555350223 ...