VCV000369919.9 - ClinVar

NM_023067.4(FOXL2):c.644A>G (p.Tyr215Cys)

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.

(4)

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/Likely 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_023067.4(FOXL2):c.644A>G (p.Tyr215Cys)

Variation ID: 369919 Accession: VCV000369919.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q22.3 3: 138946079 (GRCh38) [ NCBI UCSC ] 3: 138664921 (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	Dec 18, 2016	Nov 20, 2023	Oct 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_023067.4:c.644A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_075555.1:p.Tyr215Cys	missense
NC_000003.12:g.138946079T>C
NC_000003.11:g.138664921T>C
NG_012454.1:g.6062A>G
NG_029796.1:g.3846T>C
LRG_1295:g.6062A>G
LRG_1295t1:c.644A>G	LRG_1295p1:p.Tyr215Cys
	P58012:p.Tyr215Cys

... more HGVS ... less HGVS

Protein change

Y215C

Other names

Canonical SPDI

NC_000003.12:138946078:T:C

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

ClinGen: CA10654876 UniProtKB: P58012#VAR_021203 dbSNP: rs1057516168 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.
FOXL2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	242	277

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.
Blepharophimosis, ptosis, and epicanthus inversus syndrome	Pathogenic (1)	criteria provided, single submitter	Nov 3, 2016	RCV000408786.3
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 2, 2022	RCV000523621.7
FOXL2-related disorder	Pathogenic (1)	criteria provided, single submitter	Oct 11, 2023	RCV003392224.4

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 (Nov 03, 2016)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	Blepharophimosis, ptosis, and epicanthus inversus syndrome Affected status: yes Allele origin: germline	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000484878.1 First in ClinVar: Dec 18, 2016 Last updated: Dec 18, 2016 Comment: Clinical Testing	Number of individuals with the variant: 4
Likely pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud Accession: SCV002098085.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022	Clinical Features: Intrauterine growth restriction (present) , blepharophimosis (present) , ptosis (present) , epicanthus inversus syndrome (present) , cleft palate (present) , retrognathia (present) , small ears … (more) Intrauterine growth restriction (present) , blepharophimosis (present) , ptosis (present) , epicanthus inversus syndrome (present) , cleft palate (present) , retrognathia (present) , small ears (present) , high anterior hairline implantation (present) , hands with long fingers (present) , cutaneous umbilicus (present) , generalized decrease in subcutaneous cell tissue (present) , asymmetric sacral folds (present) , slightly anterior anus. (present) (less) Sex: female Tissue: blood Secondary finding: no
Pathogenic (Dec 13, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000617545.3 First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023	Comment: Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This … (more) Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18604817, 22312189, 30029625, 19515849, 15257268, 18484667, 27283035, 30234390) (less)
Pathogenic (Oct 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	FOXL2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004119824.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The FOXL2 c.644A>G variant is predicted to result in the amino acid substitution p.Tyr215Cys. This variant has been reported as segregating with disease in a … (more) The FOXL2 c.644A>G variant is predicted to result in the amino acid substitution p.Tyr215Cys. This variant has been reported as segregating with disease in a five generation kindred with blepharophimosis-ptosis-epicanthus inversus syndrome (Kumar et al. 2004. PubMed ID: 15257268). This variant has also been reported in a sporadic case of BPES (Wang et al. 2022. PubMed ID: 36338666). A functional study using protein expression in cell culture found that the p.Tyr215Cys substitution causes protein aggregation (Dipietromaria et al. 2009. PubMed ID: 19515849). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given all the evidence, we interpret this variant as pathogenic. (less)

Comment:

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18604817, 22312189, 30029625, 19515849, 15257268, 18484667, 27283035, 30234390)

Comment:

The FOXL2 c.644A>G variant is predicted to result in the amino acid substitution p.Tyr215Cys. This variant has been reported as segregating with disease in a five generation kindred with blepharophimosis-ptosis-epicanthus inversus syndrome (Kumar et al. 2004. PubMed ID: 15257268). This variant has also been reported in a sporadic case of BPES (Wang et al. 2022. PubMed ID: 36338666). A functional study using protein expression in cell culture found that the p.Tyr215Cys substitution causes protein aggregation (Dipietromaria et al. 2009. PubMed ID: 19515849). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given all the evidence, we interpret this variant as pathogenic.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs1057516168 ...

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 Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_023067.4(FOXL2):c.644A>G (p.Tyr215Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1057516168 ...