VCV000005343.15 - ClinVar

NM_153717.3(EVC):c.919T>C (p.Ser307Pro)

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/Likely 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_153717.3(EVC):c.919T>C (p.Ser307Pro)

Variation ID: 5343 Accession: VCV000005343.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p16.2 4: 5745321 (GRCh38) [ NCBI UCSC ] 4: 5747048 (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	Jun 17, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_153717.3:c.919T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_714928.1:p.Ser307Pro	missense
NM_001306090.2:c.919T>C	NP_001293019.1:p.Ser307Pro	missense
NM_001306092.2:c.919T>C	NP_001293021.1:p.Ser307Pro	missense
NC_000004.12:g.5745321T>C
NC_000004.11:g.5747048T>C
NG_008843.1:g.39125T>C
	P57679:p.Ser307Pro

... more HGVS ... less HGVS

Protein change

S307P

Other names

Canonical SPDI

NC_000004.12:5745320: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.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00005

Exome Aggregation Consortium (ExAC) 0.00007

Links

ClinGen: CA117420 UniProtKB: P57679#VAR_009944 OMIM: 604831.0006 dbSNP: rs121908426 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	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000005672.14
Curry-Hall syndrome Ellis-van Creveld syndrome	Pathogenic (1)	criteria provided, single submitter	Jan 16, 2024	RCV001383029.6

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 (Dec 09, 2017)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Ellis-van Creveld syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV000680219.1 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018	Zygosity: Compound Heterozygote Sex: female Tissue: blood
Likely pathogenic (Jan 05, 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: SCV000789079.1 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018	Publications: PubMed (3) PubMed: 17024374‚ 23220543‚ 10700184
Pathogenic (Jan 16, 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: SCV001582037.4 First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 10700184‚ 29321360 Comment: This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 307 of the EVC protein (p.Ser307Pro). … (more) This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 307 of the EVC protein (p.Ser307Pro). This variant is present in population databases (rs121908426, gnomAD 0.01%). This missense change has been observed in individual(s) with EVC-related conditions (PMID: 10700184, 29321360). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5343). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EVC protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Ellis-van Creveld syndrome Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005051759.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Feb 01, 2013)	no assertion criteria provided Method: literature only	ELLIS-VAN CREVELD SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025853.5 First in ClinVar: Apr 04, 2013 Last updated: Apr 21, 2017	Publications: PubMed (3) PubMed: 7628126‚ 10700184‚ 23220543 Comment on evidence: In a child with classic Ellis-van Creveld syndrome (EVC; 225500) whose father had short stature, dysplastic nails, and widely spaced conical-shaped teeth without polydactyly (WAD; … (more) In a child with classic Ellis-van Creveld syndrome (EVC; 225500) whose father had short stature, dysplastic nails, and widely spaced conical-shaped teeth without polydactyly (WAD; 193530), previously reported by Spranger and Tariverdian (1995), Ruiz-Perez et al. (2000) found compound heterozygosity for mutations in the EVC gene: a 919T-C transition in exon 7 resulting in a ser307-to-pro (S307P) substitution, which was inherited from the father, and a 1-bp deletion in exon 17, 2456delG (604831.0007), which was inherited from the mother. D'Asdia et al. (2013) reported a patient (patient 6) with classic EVC who had the S307P mutation and another mutation in the EVC gene; his father was heterozygous for S307P and was clinically unaffected. The authors stated that although S307P is a recurrent mutation in EVC, no other mutation carrier besides the father reported by Ruiz-Perez et al. (2000) had been reported to be affected. D'Asdia et al. (2013) suggested that the clinical outcome of heterozygotes may be influenced by the genetic background of each individual carrier. (less)
Pathogenic (Aug 12, 2021)	no assertion criteria provided Method: clinical testing	Ellis-van Creveld syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002083021.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 307 of the EVC protein (p.Ser307Pro). This variant is present in population databases (rs121908426, gnomAD 0.01%). This missense change has been observed in individual(s) with EVC-related conditions (PMID: 10700184, 29321360). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5343). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EVC protein function with a positive predictive value of 80%. 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 and profound deafness resulted by sequence variants in the EVC/EVC2 and TMC1 genes.	Umair M	Journal of genetics	2017	PMID: 29321360
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
Sequencing EVC and EVC2 identifies mutations in two-thirds of Ellis-van Creveld syndrome patients.	Tompson SW	Human genetics	2007	PMID: 17024374
Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis.	Ruiz-Perez VL	Nature genetics	2000	PMID: 10700184
Symptomatic heterozygosity in the Ellis-van Creveld syndrome?	Spranger S	Clinical genetics	1995	PMID: 7628126

Text-mined citations for rs121908426 ...

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_153717.3(EVC):c.919T>C (p.Ser307Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908426 ...