NM_153717.3(EVC):c.617G>A (p.Ser206Asn) AND multiple conditions

Clinical significance:Likely pathogenic (Last evaluated: Aug 30, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000548054.2

Allele description [Variation Report for NM_153717.3(EVC):c.617G>A (p.Ser206Asn)]

NM_153717.3(EVC):c.617G>A (p.Ser206Asn)

Gene:
EVC:EvC ciliary complex subunit 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
4p16.2
Genomic location:
Preferred name:
NM_153717.3(EVC):c.617G>A (p.Ser206Asn)
HGVS:
  • NC_000004.12:g.5731657G>A
  • NG_008843.1:g.25461G>A
  • NM_001306090.2:c.617G>A
  • NM_001306092.2:c.617G>A
  • NM_153717.3:c.617G>AMANE SELECT
  • NP_001293019.1:p.Ser206Asn
  • NP_001293021.1:p.Ser206Asn
  • NP_714928.1:p.Ser206Asn
  • NC_000004.11:g.5733384G>A
  • NM_153717.2:c.617G>A
Protein change:
S206N
Links:
dbSNP: rs1017946059
NCBI 1000 Genomes Browser:
rs1017946059
Molecular consequence:
  • NM_001306090.2:c.617G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001306092.2:c.617G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_153717.3:c.617G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Ellis-van Creveld syndrome (EVC)
Synonyms:
Chondroectodermal dysplasia; Mesoectodermal dysplasia
Identifiers:
MONDO: MONDO:0009162; MedGen: C0013903; Orphanet: 289; OMIM: 225500
Name:
Curry-Hall syndrome (WAD)
Synonyms:
Acrofacial dysostosis of Weyers; WEYERS ACRODENTAL DYSOSTOSIS
Identifiers:
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)
OriginMethodCitations
SCV000626063Invitaecriteria provided, single submitter
Likely pathogenic
(Aug 30, 2017)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

A novel missense mutation in the EVC gene underlies Ellis-van Creveld syndrome in a Pakistani family.

Umm-E-Kalsoom, Wasif N, Tariq M, Ahmad W.

Pediatr Int. 2010 Apr;52(2):240-6. doi: 10.1111/j.1442-200X.2009.02953.x. Epub 2009 Sep 7.

PubMed [citation]
PMID:
19744229

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000626063.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces serine with asparagine at codon 206 of the EVC protein (p.Ser206Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant also falls at the last nucleotide of exon 4 of the EVC coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Ellis-van Creveld syndrome in a single family (PMID: 19744229). The variant was homozygous in 3 affected siblings, while the unaffected parents were heterozygous carriers. This variant occurs with a likely pathogenic variant (p.Lys302del) in EVC in an individual with clinical features consistent with an EVC-related disease. Manual review of the sequencing data indicates that these two variants are on opposite chromosomes (in trans), which suggests the c.617G>A substitution may contribute to disease. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change at a consensus splice site that has been observed to segregate with disease and observed in trans with a likely pathogenic variant. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Jan 8, 2022

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