VCV000349176.50 - ClinVar

NM_153717.3(EVC):c.1369G>A (p.Glu457Lys)

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.

(11)

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.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(2); Likely benign(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_153717.3(EVC):c.1369G>A (p.Glu457Lys)

Variation ID: 349176 Accession: VCV000349176.50

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p16.2 4: 5753838 (GRCh38) [ NCBI UCSC ] 4: 5755565 (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	Dec 6, 2016	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_153717.3:c.1369G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_714928.1:p.Glu457Lys	missense
NM_001306090.2:c.1369G>A	NP_001293019.1:p.Glu457Lys	missense
NM_001306092.2:c.1369G>A	NP_001293021.1:p.Glu457Lys	missense
NC_000004.12:g.5753838G>A
NC_000004.11:g.5755565G>A
NG_008843.1:g.47642G>A

... more HGVS ... less HGVS

Protein change

E457K

Other names

Canonical SPDI

NC_000004.12:5753837: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.

0.00100 (A)

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

1000 Genomes Project 30x 0.00078

1000 Genomes Project 0.00100

The Genome Aggregation Database (gnomAD) 0.00188

Trans-Omics for Precision Medicine (TOPMed) 0.00204

The Genome Aggregation Database (gnomAD), exomes 0.00208

Exome Aggregation Consortium (ExAC) 0.00213

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00284

Links

ClinGen: CA2836082 dbSNP: rs141859946 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.
EVC		-	-	GRCh38 GRCh37	1808	1959

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	Likely benign (2)	criteria provided, single submitter	Jan 13, 2018	RCV000356036.15
not specified	Likely benign (1)	criteria provided, single submitter	Aug 17, 2017	RCV000609966.12
Curry-Hall syndrome Ellis-van Creveld syndrome	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jan 31, 2024	RCV000542079.25
not provided	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV001573985.27
EVC-related disorder	Likely benign (1)	no assertion criteria provided	Jun 13, 2019	RCV003902350.2

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.
Uncertain significance (Jun 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ellis-van Creveld syndrome Curry-Hall syndrome Affected status: unknown Allele origin: maternal	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000782673.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018
Likely benign (Aug 17, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000856209.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Publications: PubMed (1) PubMed: 24431330 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=EVC http://gnomad.broadinstitute.org… http://gnomad.broadinstitute.org/region/4-5755465-5755665 Number of individuals with the variant: 1 Sex: mixed
Likely benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Ellis-van Creveld syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000450258.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Benign (Mar 25, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000714050.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Likely benign (Nov 29, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000883810.3 First in ClinVar: Feb 18, 2019 Last updated: Feb 20, 2024
Benign (Jan 31, 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: SCV000634716.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024
Likely benign (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004147612.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: EVC: BP4, BS2 Number of individuals with the variant: 5
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001800640.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001968929.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Benign (Oct 21, 2019)	no assertion criteria provided Method: clinical testing	Ellis-van Creveld syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002083028.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Likely benign (Jun 13, 2019)	no assertion criteria provided Method: clinical testing	EVC-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004733266.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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
Truncating mutations in TAF4B and ZMYND15 causing recessive azoospermia.	Ayhan Ö	Journal of medical genetics	2014	PMID: 24431330
http://gnomad.broadinstitute.org/region/4-5755465-5755665	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=EVC	-	-	-	-

Text-mined citations for rs141859946 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_153717.3(EVC):c.1369G>A (p.Glu457Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs141859946 ...