VCV000003383.21 - ClinVar

NM_147127.5(EVC2):c.1195C>T (p.Arg399Ter)

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.

(12)

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.1195C>T (p.Arg399Ter)

Variation ID: 3383 Accession: VCV000003383.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p16.2 4: 5640789 (GRCh38) [ NCBI UCSC ] 4: 5642516 (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 21, 2017	Feb 28, 2024	Jan 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_147127.5:c.1195C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_667338.3:p.Arg399Ter	nonsense
NM_001166136.2:c.955C>T	NP_001159608.1:p.Arg319Ter	nonsense
NC_000004.12:g.5640789G>A
NC_000004.11:g.5642516G>A
NG_015821.1:g.73760C>T

... more HGVS ... less HGVS

Protein change

R399*, R319*

Other names

Canonical SPDI

NC_000004.12:5640788:G:A

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.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00005

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA116164 OMIM: 607261.0004 dbSNP: rs137852924 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
LOC126806961	-	-	-	GRCh38	-	177

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/Likely pathogenic (5)	no assertion criteria provided	Jun 1, 2017	RCV000003550.11
Short-rib thoracic dysplasia 6 with or without polydactyly	Pathogenic/Likely pathogenic (2)	no assertion criteria provided	Jun 1, 2017	RCV000516144.4
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 22, 2021	RCV000578498.8
Curry-Hall syndrome Ellis-van Creveld syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 4, 2024	RCV000763528.11

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 31, 2018)	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: SCV000894340.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Jul 22, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000680767.2 First in ClinVar: Feb 13, 2018 Last updated: Feb 13, 2018	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33452237, 29068549, 21199751, 23276573, 12571802, 17024374, 23026208, 25525159) (less)
Pathogenic (Jan 25, 2018)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000859321.1 First in ClinVar: Feb 13, 2018 Last updated: Feb 13, 2018	Publications: PubMed (1) PubMed: 12571802 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=EVC2 Number of individuals with the variant: 1 Sex: mixed
Pathogenic (May 22, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002501386.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (4) PubMed: 12571802‚ 21199751‚ 25525159‚ 29068549 Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (Jan 04, 2024)	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: SCV000626058.6 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (6) PubMed: 17024374‚ 19810119‚ 19876929‚ 12571802‚ 21199751‚ 23026208 Comment: This sequence change creates a premature translational stop signal (p.Arg399) in the EVC2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg399) in the EVC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EVC2 are known to be pathogenic (PMID: 17024374, 19810119, 19876929). This variant is present in population databases (rs137852924, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Ellis-van Creveld syndrome (PMID: 12571802, 21199751, 23026208). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3383). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 08, 2017)	no assertion criteria provided Method: clinical testing	Ellis-van Creveld syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000791341.2 First in ClinVar: Dec 26, 2017 Last updated: Dec 23, 2019	Publications: PubMed (2) PubMed: 21199751‚ 22190900
Likely pathogenic (-)	no assertion criteria provided Method: research	Ellis van Creveld syndrome Affected status: yes Allele origin: inherited	University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV001479600.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021	Publications: PubMed (1) PubMed: 29068549
Likely pathogenic (-)	no assertion criteria provided Method: research	short-rib polydactyly syndrome type II Affected status: yes Allele origin: inherited	University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV001479761.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021	Publications: PubMed (1) PubMed: 29068549
Pathogenic (Mar 01, 2003)	no assertion criteria provided Method: literature only	ELLIS-VAN CREVELD SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023708.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 21, 2017	Publications: PubMed (1) PubMed: 12571802 Comment on evidence: In a stillborn child with Ellis-van Creveld syndrome (225500) who had ventricular septal defect and short limbs with postaxial polydactyly of the hands and radiographic … (more) In a stillborn child with Ellis-van Creveld syndrome (225500) who had ventricular septal defect and short limbs with postaxial polydactyly of the hands and radiographic features typical of EVC, with short limbs and classic pelvic configuration, Ruiz-Perez et al. (2003) found an 1195C-T transition in exon 10 of the EVC2 gene that introduced a nonsense codon (arg399 to stop). (less)
Pathogenic (Jun 01, 2017)	no assertion criteria provided Method: research	Short-rib thoracic dysplasia 6 with or without polydactyly Affected status: yes Allele origin: unknown	Dan Cohn Lab, University Of California Los Angeles Accession: SCV000612085.1 First in ClinVar: Dec 10, 2017 Last updated: Dec 10, 2017	Publications: PubMed (1) PubMed: 29068549 Observation 1: Observation 2:
Pathogenic (Jun 01, 2017)	no assertion criteria provided Method: research	Ellis-van Creveld Syndrome Affected status: yes Allele origin: biparental	Dan Cohn Lab, University Of California Los Angeles Accession: SCV000612086.1 First in ClinVar: Dec 10, 2017 Last updated: Dec 10, 2017	Publications: PubMed (1) PubMed: 29068549
Pathogenic (-)	no assertion criteria provided Method: literature only	Ellis-van Creveld syndrome Affected status: unknown Allele origin: paternal	Prenatal Diagnosis Center, International Peace Maternity & Child Health Hospital Accession: SCV004037445.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023	Publications: PubMed (1) PubMed: 35927022
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Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33452237, 29068549, 21199751, 23276573, 12571802, 17024374, 23026208, 25525159)

Comment:

This sequence change creates a premature translational stop signal (p.Arg399*) in the EVC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EVC2 are known to be pathogenic (PMID: 17024374, 19810119, 19876929). This variant is present in population databases (rs137852924, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Ellis-van Creveld syndrome (PMID: 12571802, 21199751, 23026208). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3383). 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
Ellis-Van Creveld Syndrome: Clinical and Molecular Analysis of 50 Individuals.	Aubert-Mucca M	Journal of medical genetics	2023	PMID: 35927022
Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies.	Zhang W	Human mutation	2018	PMID: 29068549
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
Identification of one novel mutation in the EVC2 gene in a Chinese family with Ellis-van Creveld syndrome.	Zhang Z	Gene	2012	PMID: 23026208
Two Adult Patients with Ellis-van Creveld Syndrome Extending the Clinical Spectrum.	Rudnik-Schöneborn S	Molecular syndromology	2011	PMID: 22190900
Ellis-van Creveld syndrome: prenatal diagnosis, molecular analysis and genetic counseling.	Chen CP	Taiwanese journal of obstetrics & gynecology	2010	PMID: 21199751
Ellis-van Creveld syndrome and Weyers acrodental dysostosis are caused by cilia-mediated diminished response to hedgehog ligands.	Ruiz-Perez VL	American journal of medical genetics. Part C, Seminars in medical genetics	2009	PMID: 19876929
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
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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=EVC2	-	-	-	-
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Text-mined citations for rs137852924 ...

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.1195C>T (p.Arg399Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137852924 ...