VCV000267443.12 - ClinVar

NM_006494.4(ERF):c.266A>G (p.Tyr89Cys)

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.

(7)

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_006494.4(ERF):c.266A>G (p.Tyr89Cys)

Variation ID: 267443 Accession: VCV000267443.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.2 19: 42249934 (GRCh38) [ NCBI UCSC ] 19: 42754086 (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	Feb 25, 2017	Jun 9, 2024	Mar 6, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_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
NC_000019.10:g.42249934T>C
NC_000019.9:g.42754086T>C
NG_042802.1:g.10231A>G

... more HGVS ... less HGVS

Protein change

Y89C, Y14C

Other names

Canonical SPDI

NC_000019.10:42249933: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: CA10602507 OMIM: 611888.0008 dbSNP: rs886041001 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.
ERF		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	210	224

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.
Chitayat syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Mar 6, 2024	RCV000258152.7
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 6, 2022	RCV000481720.6
Inborn genetic diseases	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.
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) 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 (GeneDx Variant Classification Process June 2021) 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)
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) 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	Publications: PubMed (2) PubMed: 27738187‚ 30569521 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)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) 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
Pathogenic (Dec 17, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) 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	Publications: PubMed (4) PubMed: 27738187‚ 30569521‚ 30728880‚ 32592542 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)
Pathogenic (Mar 06, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) 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 (Feb 21, 2017)	no assertion criteria provided Method: literature only	CHITAYAT SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000328354.2 First in ClinVar: Nov 06, 2016 Last updated: Feb 25, 2017	Publications: PubMed (2) PubMed: 8418638‚ 27738187 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:

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.

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
Variable pulmonary manifestations in Chitayat syndrome: Six additional affected individuals.	Suter AA	American journal of medical genetics. Part A	2020	PMID: 32592542
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 ...

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_006494.4(ERF):c.266A>G (p.Tyr89Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886041001 ...