NM_147127.5(EVC2):c.450+2T>C AND multiple conditions

Clinical significance:Likely pathogenic (Last evaluated: Dec 7, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_147127.5(EVC2):c.450+2T>C]


EVC2:EvC ciliary complex subunit 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000004.12:g.5694333A>G
  • NG_015821.1:g.20216T>C
  • NM_001166136.2:c.210+2T>C
  • NM_147127.5:c.450+2T>CMANE SELECT
  • NC_000004.11:g.5696060A>G
  • NM_147127.4:c.450+2T>C
dbSNP: rs781096099
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001166136.2:c.210+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_147127.5:c.450+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]


Ellis-van Creveld syndrome (EVC)
Chondroectodermal dysplasia; Mesoectodermal dysplasia
MONDO: MONDO:0009162; MedGen: C0013903; Orphanet: 289; OMIM: 225500
Curry-Hall syndrome (WAD)
Acrofacial dysostosis of Weyers; WEYERS ACRODENTAL DYSOSTOSIS
MONDO: MONDO:0008673; MedGen: C0457013; Orphanet: 952; OMIM: 193530

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000946009Invitaecriteria provided, single submitter
Likely pathogenic
(Dec 7, 2018)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



Sequencing EVC and EVC2 identifies mutations in two-thirds of Ellis-van Creveld syndrome patients.

Tompson SW, Ruiz-Perez VL, Blair HJ, Barton S, Navarro V, Robson JL, Wright MJ, Goodship JA.

Hum Genet. 2007 Jan;120(5):663-70. Epub 2006 Sep 21.

PubMed [citation]

Widening the mutation spectrum of EVC and EVC2: ectopic expression of Weyer variants in NIH 3T3 fibroblasts disrupts Hedgehog signaling.

Valencia M, Lapunzina P, Lim D, Zannolli R, Bartholdi D, Wollnik B, Al-Ajlouni O, Eid SS, Cox H, Buoni S, Hayek J, Martinez-Frias ML, Antonio PA, Temtamy S, Aglan M, Goodship JA, Ruiz-Perez VL.

Hum Mutat. 2009 Dec;30(12):1667-75. doi: 10.1002/humu.21117.

PubMed [citation]
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000946009.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)


This sequence change affects a donor splice site in intron 3 of the EVC2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with EVC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 554626). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EVC2 are known to be pathogenic (PMID: 17024374, 19810119, 19876929). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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