VCV000021247.19 - ClinVar

NM_001017420.3(ESCO2):c.760del (p.Thr254fs)

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.

(8)

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_001017420.3(ESCO2):c.760del (p.Thr254fs)

Variation ID: 21247 Accession: VCV000021247.19

Type and length

Deletion, 1 bp

Location

Cytogenetic: 8p21.1 8: 27777060 (GRCh38) [ NCBI UCSC ] 8: 27634577 (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	Feb 14, 2024	Jan 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001017420.3:c.760del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001017420.1:p.Thr254fs	frameshift
NC_000008.11:g.27777068del
NC_000008.10:g.27634585del
NG_008117.1:g.7528del

Protein change

T254fs

Other names

p.K253fsX12

Canonical SPDI

NC_000008.11:27777059:AAAAAAAAA:AAAAAAAA

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: CA341793 OMIM: 609353.0007 dbSNP: rs80359852 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.
ESCO2		-	-	GRCh38 GRCh37	634	725

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.
Roberts-SC phocomelia syndrome	Pathogenic (3)	criteria provided, single submitter	Feb 8, 2013	RCV000020409.13
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 29, 2024	RCV000593748.13
Roberts syndrome	Pathogenic (1)	no assertion criteria provided	Nov 28, 2020	RCV001826485.2

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 (May 14, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000778962.2 First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018	Comment: The c.760delA variant (also known as c.752delA due to alternate nomenclature) in the ESCO2 gene has been reported previously with a second variant in ESCO2 … (more) The c.760delA variant (also known as c.752delA due to alternate nomenclature) in the ESCO2 gene has been reported previously with a second variant in ESCO2 in several unrelated individuals with diagnoses of Roberts-SC phocomelia syndrome (Schule et al., 2005; Gordillo et al., 2008). The c.760delA variant causes a frameshift starting with codon Threonine 254, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Thr254LeufsX13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.760delA variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.760delA as a pathogenic variant. (less)
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001588718.3 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 15821733‚ 16380922‚ 18411254 Comment: This sequence change creates a premature translational stop signal (p.Thr254Leufs13) in the ESCO2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Thr254Leufs13) in the ESCO2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ESCO2 are known to be pathogenic (PMID: 15821733, 16380922). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Roberts syndrome (PMID: 16380922, 18411254). This variant is also known as c.752delA and p.K253fsX12. ClinVar contains an entry for this variant (Variation ID: 21247). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 08, 2013)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	Roberts syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000193114.1 First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014
Pathogenic (Jan 12, 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: SCV000705576.2 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=ESCO2 Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Nov 25, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002022211.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Dec 01, 2005)	no assertion criteria provided Method: literature only	ROBERTS-SC PHOCOMELIA SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000021967.4 First in ClinVar: Apr 04, 2013 Last updated: Feb 27, 2021	Publications: PubMed (1) PubMed: 16380922 Comment on evidence: For discussion of the 1-bp deletion (752delA) in the ESCO2 gene that was found in compound heterozygous state in patients with Roberts-SC phocomelia syndrome (RBS; … (more) For discussion of the 1-bp deletion (752delA) in the ESCO2 gene that was found in compound heterozygous state in patients with Roberts-SC phocomelia syndrome (RBS; 268300) by Schule et al. (2005), see 609353.0006. (less)
Pathogenic (Nov 28, 2020)	no assertion criteria provided Method: clinical testing	Roberts syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002083246.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022
not provided (-)	no classification provided Method: literature only	Roberts-SC phocomelia syndrome Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000040809.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (3) PubMed: 16380922‚ 18411254‚ 20301332 BookShelf: NBK1153 BookShelf: NBK1153

Comment:

The c.760delA variant (also known as c.752delA due to alternate nomenclature) in the ESCO2 gene has been reported previously with a second variant in ESCO2 in several unrelated individuals with diagnoses of Roberts-SC phocomelia syndrome (Schule et al., 2005; Gordillo et al., 2008). The c.760delA variant causes a frameshift starting with codon Threonine 254, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Thr254LeufsX13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.760delA variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.760delA as a pathogenic variant.

Comment:

This sequence change creates a premature translational stop signal (p.Thr254Leufs*13) in the ESCO2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ESCO2 are known to be pathogenic (PMID: 15821733, 16380922). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Roberts syndrome (PMID: 16380922, 18411254). This variant is also known as c.752delA and p.K253fsX12. ClinVar contains an entry for this variant (Variation ID: 21247). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been 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
ESCO2 Spectrum Disorder.	Adam MP	-	2020	PMID: 20301332
The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity.	Gordillo M	Human molecular genetics	2008	PMID: 18411254
Inactivating mutations in ESCO2 cause SC phocomelia and Roberts syndrome: no phenotype-genotype correlation.	Schüle B	American journal of human genetics	2005	PMID: 16380922
Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion.	Vega H	Nature genetics	2005	PMID: 15821733
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ESCO2	-	-	-	-

Text-mined citations for rs80359852 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001017420.3(ESCO2):c.760del (p.Thr254fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80359852 ...