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: 30569521, 27738187, 30728880, 30758909, 32592542, 34426522, 31785789)
ClinVar Genomic variation as it relates to human health
NM_006494.4(ERF):c.266A>G (p.Tyr89Cys)
Germline
Classification
Help
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.
(8)
Help
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006494.4(ERF):c.266A>G (p.Tyr89Cys)
Variation ID: 267443 Accession: VCV000267443.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 42754086 (GRCh37) [ NCBI UCSC ] 19: 42249934 (GRCh38) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Feb 25, 2017 Nov 24, 2024 Oct 10, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006494.4:c.266A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006485.2:p.Tyr89Cys missense NM_001301035.2:c.41A>G NP_001287964.1:p.Tyr14Cys missense NM_001308402.2:c.41A>G NP_001295331.1:p.Tyr14Cys missense NM_001312656.2:c.41A>G NP_001299585.1:p.Tyr14Cys missense NM_006494.3:c.266A>G NC_000019.10:g.42249934T>C NC_000019.9:g.42754086T>C NG_042802.1:g.10231A>G - Protein change
- Y89C, Y14C
- Other names
- -
- Canonical SPDI
- NC_000019.10:42249933:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| ERF | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
216 | 230 | |
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. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 10, 2024 | RCV000258152.8 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 6, 2022 | RCV000481720.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 17, 2021 | RCV002518789.2 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447676.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Microcephaly (present) , Intellectual disability (present) , Global developmental delay (present) , Short stature (present)
Sex: male
|
|
|
Pathogenic
(Jul 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000570938.8
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
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: 30569521, 27738187, 30728880, 30758909, 32592542, 34426522, 31785789) (less)
|
|
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Pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Chitayat syndrome
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002318522.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000267443). The … (more)
Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000267443). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 30569521, 27738187). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.764>=0.6, 3CNET: 0.97>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Abnormal pulmonary thoracic imaging finding (present) , Gastroesophageal reflux (present) , Congenital laryngomalacia (present) , Postterm pregnancy (present) , Abnormality of pulmonary circulation (present) , … (more)
Abnormal pulmonary thoracic imaging finding (present) , Gastroesophageal reflux (present) , Congenital laryngomalacia (present) , Postterm pregnancy (present) , Abnormality of pulmonary circulation (present) , Recurrent lower respiratory tract infections (present) , Respiratory distress (present) (less)
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Chitayat syndrome
Affected status: yes
Allele origin:
maternal
|
Molecular Genetics Lab, CHRU Brest
Accession: SCV004697643.1
First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024 |
|
|
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Pathogenic
(Dec 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003564122.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.266A>G (p.Y89C) alteration is located in exon 3 (coding exon 3) of the ERF gene. This alteration results from a A to G substitution … (more)
The c.266A>G (p.Y89C) alteration is located in exon 3 (coding exon 3) of the ERF gene. This alteration results from a A to G substitution at nucleotide position 266, causing the tyrosine (Y) at amino acid position 89 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration is a recurrent alteration reported in multiple unrelated individuals with Chitayat syndrome. This alteration occurred de novo in at least three separate patients and was inherited from an affected parent in two families (Balasubramanian, 2016; Caro-Contreras, 2019; Shin, 2019; Suter, 2020; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Mar 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Chitayat syndrome
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005049277.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
|
|
|
Pathogenic
(Oct 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Chitayat syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005398927.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with craniosynostosis 4 (MIM#600775). A single recurring missense variant has been reported to cause Chitayat syndrome (MIM#617180), where the mechanism is unclear (PMID: 27738187). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance in some families with craniosynostosis (PMID: 30758909). (I) 0115 - Variants in this gene are known to have variable expressivity, with intrafamilial variability reported for craniosynostosis (PMID: 35852485). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Ets domain (DECIPHER]. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and has been observed as de novo or inherited from an affected parent in the literature in individuals with Chitayat syndrome (PMID: 27738187). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Feb 21, 2017)
|
no assertion criteria provided
Method: literature only
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CHITAYAT SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000328354.2
First in ClinVar: Nov 06, 2016 Last updated: Feb 25, 2017 |
Comment on evidence:
In 5 patients from 4 families with Chitayat syndrome (CHYTS; 617180), including the patient originally described by Chitayat et al. (1993), Balasubramanian et al. (2017) … (more)
In 5 patients from 4 families with Chitayat syndrome (CHYTS; 617180), including the patient originally described by Chitayat et al. (1993), Balasubramanian et al. (2017) identified heterozygosity for a c.266A-G (c.266A-G, NM_006494.2) transition in the ERF gene, resulting in a tyr89-to-cys (Y89C) substitution at a highly conserved residue within the DNA-binding ETS domain. The mutation, which was detected in an affected father and son in 1 of the families, was confirmed to have occurred de novo in the remaining 3 patients. Investigations including CT scans of the skull detected no evidence of craniosynostosis in any of the patients. (less)
|
Comment:
Comment:
Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000267443). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 30569521, 27738187). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.764>=0.6, 3CNET: 0.97>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The c.266A>G (p.Y89C) alteration is located in exon 3 (coding exon 3) of the ERF gene. This alteration results from a A to G substitution at nucleotide position 266, causing the tyrosine (Y) at amino acid position 89 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration is a recurrent alteration reported in multiple unrelated individuals with Chitayat syndrome. This alteration occurred de novo in at least three separate patients and was inherited from an affected parent in two families (Balasubramanian, 2016; Caro-Contreras, 2019; Shin, 2019; Suter, 2020; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with craniosynostosis 4 (MIM#600775). A single recurring missense variant has been reported to cause Chitayat syndrome (MIM#617180), where the mechanism is unclear (PMID: 27738187). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance in some families with craniosynostosis (PMID: 30758909). (I) 0115 - Variants in this gene are known to have variable expressivity, with intrafamilial variability reported for craniosynostosis (PMID: 35852485). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Ets domain (DECIPHER]. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and has been observed as de novo or inherited from an affected parent in the literature in individuals with Chitayat syndrome (PMID: 27738187). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
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:
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: 30569521, 27738187, 30728880, 30758909, 32592542, 34426522, 31785789)
Comment:
Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000267443). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 30569521, 27738187). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.764>=0.6, 3CNET: 0.97>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The c.266A>G (p.Y89C) alteration is located in exon 3 (coding exon 3) of the ERF gene. This alteration results from a A to G substitution at nucleotide position 266, causing the tyrosine (Y) at amino acid position 89 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration is a recurrent alteration reported in multiple unrelated individuals with Chitayat syndrome. This alteration occurred de novo in at least three separate patients and was inherited from an affected parent in two families (Balasubramanian, 2016; Caro-Contreras, 2019; Shin, 2019; Suter, 2020; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with craniosynostosis 4 (MIM#600775). A single recurring missense variant has been reported to cause Chitayat syndrome (MIM#617180), where the mechanism is unclear (PMID: 27738187). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance in some families with craniosynostosis (PMID: 30758909). (I) 0115 - Variants in this gene are known to have variable expressivity, with intrafamilial variability reported for craniosynostosis (PMID: 35852485). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Ets domain (DECIPHER]. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and has been observed as de novo or inherited from an affected parent in the literature in individuals with Chitayat syndrome (PMID: 27738187). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Intrafamilial variability in six family members with ERF-related craniosynostosis syndrome type 4. | Moddemann MK | American journal of medical genetics. Part A | 2022 | PMID: 35852485 |
| Variable pulmonary manifestations in Chitayat syndrome: Six additional affected individuals. | Suter AA | American journal of medical genetics. Part A | 2020 | PMID: 32592542 |
| ERF-related craniosynostosis: The phenotypic and developmental profile of a new craniosynostosis syndrome. | Glass GE | American journal of medical genetics. Part A | 2019 | PMID: 30758909 |
| Radiography of Chitayat syndrome in an infant male. | Shin SH | Radiology case reports | 2019 | PMID: 30728880 |
| Molecular analysis provides further evidence that Chitayat syndrome is caused by the recurrent p.(Tyr89Cys) pathogenic variant in the ERF gene. | Caro-Contreras A | American journal of medical genetics. Part A | 2019 | PMID: 30569521 |
| Chitayat syndrome: hyperphalangism, characteristic facies, hallux valgus and bronchomalacia results from a recurrent c.266A>G p.(Tyr89Cys) variant in the ERF gene. | Balasubramanian M | Journal of medical genetics | 2017 | PMID: 27738187 |
| Hyperphalangism, facial anomalies, hallux valgus, and bronchomalacia: a new syndrome? | Chitayat D | American journal of medical genetics | 1993 | PMID: 8418638 |
Text-mined citations for rs886041001 ...
HelpThese 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 Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.