VCV000553833.12 - ClinVar

NM_147127.5(EVC2):c.3660del (p.Ser1220fs)

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.

(6)

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_147127.5(EVC2):c.3660del (p.Ser1220fs)

Variation ID: 553833 Accession: VCV000553833.12

Type and length

Deletion, 1 bp

Location

Cytogenetic: 4p16.2 4: 5563115 (GRCh38) [ NCBI UCSC ] 4: 5564842 (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	Aug 5, 2018	Feb 28, 2024	Oct 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_147127.5:c.3660del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_667338.3:p.Ser1220fs	frameshift
NM_001166136.2:c.3420del	NP_001159608.1:p.Ser1140fs	frameshift
NM_147127.4:c.3660del
NC_000004.12:g.5563115del
NC_000004.11:g.5564842del
NG_015821.1:g.151434del

... more HGVS ... less HGVS

Protein change

S1140fs, S1220fs

Other names

AY185210.1:c.3660del

Canonical SPDI

NC_000004.12:5563114:G:

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

Links

OMIM: 607261.0001 dbSNP: rs753581033 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.
EVC2		-	-	GRCh38 GRCh37	1843	2116

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.
Ellis-van Creveld syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 8, 2022	RCV000669358.4
not provided	Pathogenic (1)	criteria provided, single submitter	Mar 1, 2021	RCV001553071.3
Curry-Hall syndrome Ellis-van Creveld syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 27, 2023	RCV001214869.8

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 (Sep 13, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Ellis-van Creveld syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000794105.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (1) PubMed: 19810119
Pathogenic (Mar 01, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001773875.1 First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021	Comment: Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 89 amino acids are lost and replaced with 2 incorrect amino … (more) Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 89 amino acids are lost and replaced with 2 incorrect amino acids (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 19810119, 17024374, 12571802, 19876929, 23220543) (less)
Pathogenic (Sep 08, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Ellis-van Creveld syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002599016.1 First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022	Publications: PubMed (2) PubMed: 12571802‚ 19810119 Comment: Variant summary: EVC2 c.3660delC (p.Ser1220ArgfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: EVC2 c.3660delC (p.Ser1220ArgfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar database. The variant allele was found at a frequency of 2e-05 in 250124 control chromosomes (gnomAD). c.3660delC has been reported in the literature in multiple individuals affected with Ellis-Van Creveld Syndrome, including homozygotes (Ruiz-Perez_2003, Valencia_2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Mar 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Curry-Hall syndrome Ellis-van Creveld syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002805346.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Oct 27, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Curry-Hall syndrome Ellis-van Creveld syndrome Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001386574.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 12571802‚ 17024374‚ 19810119‚ 23220543‚ 16404586 Comment: This sequence change creates a premature translational stop signal (p.Ser1220Argfs3) in the EVC2 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Ser1220Argfs3) in the EVC2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 89 amino acid(s) of the EVC2 protein. This variant is present in population databases (rs753581033, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with autosomal recessive Ellis-van Creveld syndrome (PMID: 12571802, 17024374, 19810119, 23220543). This variant is also known as c.3660delC. ClinVar contains an entry for this variant (Variation ID: 553833). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the EVC2 protein in which other variant(s) (p.Leu1265Tyrfs*2) have been determined to be pathogenic (PMID: 16404586). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 01, 2003)	no assertion criteria provided Method: literature only	ELLIS-VAN CREVELD SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023705.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 12571802 Comment on evidence: In a consanguineous Gypsy pedigree, Ruiz-Perez et al. (2003) found that members with Ellis-van Creveld syndrome (225500) had a frameshift mutation (3660delC) in exon 22 … (more) In a consanguineous Gypsy pedigree, Ruiz-Perez et al. (2003) found that members with Ellis-van Creveld syndrome (225500) had a frameshift mutation (3660delC) in exon 22 of the gene they characterized and designated EVC2. The clinical features in affected individuals in this family included atrioventricular septal defects, mesomelic limb shortening with genu valgum, polydactyly with nail dysplasia, multiple oral frenula, and dysplastic teeth. Two affected individuals in earlier generations were said to have postaxial polydactyly and congenital heart defects but no other features of EVC. (less)

Comment:

Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 89 amino acids are lost and replaced with 2 incorrect amino acids (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 19810119, 17024374, 12571802, 19876929, 23220543)

Comment:

Variant summary: EVC2 c.3660delC (p.Ser1220ArgfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar database. The variant allele was found at a frequency of 2e-05 in 250124 control chromosomes (gnomAD). c.3660delC has been reported in the literature in multiple individuals affected with Ellis-Van Creveld Syndrome, including homozygotes (Ruiz-Perez_2003, Valencia_2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Ser1220Argfs*3) in the EVC2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 89 amino acid(s) of the EVC2 protein. This variant is present in population databases (rs753581033, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with autosomal recessive Ellis-van Creveld syndrome (PMID: 12571802, 17024374, 19810119, 23220543). This variant is also known as c.3660delC. ClinVar contains an entry for this variant (Variation ID: 553833). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the EVC2 protein in which other variant(s) (p.Leu1265Tyrfs*2) have been determined to be pathogenic (PMID: 16404586). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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
Novel and recurrent EVC and EVC2 mutations in Ellis-van Creveld syndrome and Weyers acrofacial dyostosis.	D'Asdia MC	European journal of medical genetics	2013	PMID: 23220543
Widening the mutation spectrum of EVC and EVC2: ectopic expression of Weyer variants in NIH 3T3 fibroblasts disrupts Hedgehog signaling.	Valencia M	Human mutation	2009	PMID: 19810119
Sequencing EVC and EVC2 identifies mutations in two-thirds of Ellis-van Creveld syndrome patients.	Tompson SW	Human genetics	2007	PMID: 17024374
A novel heterozygous deletion in the EVC2 gene causes Weyers acrofacial dysostosis.	Ye X	Human genetics	2006	PMID: 16404586
Mutations in two nonhomologous genes in a head-to-head configuration cause Ellis-van Creveld syndrome.	Ruiz-Perez VL	American journal of human genetics	2003	PMID: 12571802

Text-mined citations for rs753581033 ...

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_147127.5(EVC2):c.3660del (p.Ser1220fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs753581033 ...