NM_020928.2(ZSWIM6):c.3487C>T (p.Arg1163Trp) AND Acromelic frontonasal dysostosis

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: May 31, 2018)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000143865.8

Allele description [Variation Report for NM_020928.2(ZSWIM6):c.3487C>T (p.Arg1163Trp)]

NM_020928.2(ZSWIM6):c.3487C>T (p.Arg1163Trp)

Gene:
ZSWIM6:zinc finger SWIM-type containing 6 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
5q12.1
Genomic location:
Preferred name:
NM_020928.2(ZSWIM6):c.3487C>T (p.Arg1163Trp)
HGVS:
  • NC_000005.10:g.61544156C>T
  • NG_053150.1:g.216884C>T
  • NM_020928.2:c.3487C>TMANE SELECT
  • NP_065979.1:p.Arg1163Trp
  • NC_000005.9:g.60839983C>T
  • NM_020928.1:c.3487C>T
  • Q9HCJ5:p.Arg1163Trp
Protein change:
R1163W; ARG1163TRP
Links:
UniProtKB: Q9HCJ5#VAR_071802; OMIM: 615951.0001; dbSNP: rs587777695
NCBI 1000 Genomes Browser:
rs587777695
Molecular consequence:
  • NM_020928.2:c.3487C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Acromelic frontonasal dysostosis (AFND)
Identifiers:
MONDO: MONDO:0011359; MedGen: C1863616; Orphanet: 1827; OMIM: 603671

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000188733OMIMno assertion criteria providedPathogenic
(Aug 7, 2014)
germlineliterature only

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

SCV000246129University of Washington Center for Mendelian Genomics, University of Washingtoncriteria provided, single submitter
Pathogenic
(Sep 23, 2014)
de novoresearch

PubMed (1)
[See all records that cite this PMID]

SCV000803459SIB Swiss Institute of Bioinformaticscriteria provided, single submitter
Likely pathogenic
(May 31, 2018)
unknowncuration

PubMed (3)
[See all records that cite these PMIDs]

SCV000803852Equipe Genetique des Anomalies du Developpement, Université de Bourgogne - Clinvar_gadteam_Clinical_exome_analysis_3criteria provided, single submitter
Pathogenic
(Oct 11, 2017)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000986913GenomeConnect, ClinGenno assertion providednot providedunknownphenotyping only

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedunknownunknownnot providednot providednot providednot providednot providedcuration, phenotyping only
not providedde novoyesnot providednot providednot providednot providednot providedresearch

Citations

PubMed

Exome sequencing identifies a recurrent de novo ZSWIM6 mutation associated with acromelic frontonasal dysostosis.

Smith JD, Hing AV, Clarke CM, Johnson NM, Perez FA, Park SS, Horst JA, Mecham B, Maves L, Nickerson DA; University of Washington Center for Mendelian Genomics., Cunningham ML.

Am J Hum Genet. 2014 Aug 7;95(2):235-40. doi: 10.1016/j.ajhg.2014.07.008.

PubMed [citation]
PMID:
25105228
PMCID:
PMC4129399

Acromelic frontonasal dysostosis and ZSWIM6 mutation: phenotypic spectrum and mosaicism.

Twigg SR, Ousager LB, Miller KA, Zhou Y, Elalaoui SC, Sefiani A, Bak GS, Hove H, Hansen LK, Fagerberg CR, Tajir M, Wilkie AO.

Clin Genet. 2016 Sep;90(3):270-5. doi: 10.1111/cge.12721. Epub 2016 Feb 3.

PubMed [citation]
PMID:
26706854
PMCID:
PMC5025718
See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000188733.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

In 4 unrelated patients with acromelic frontonasal dysostosis (AFND; 603671), Smith et al. (2014) identified heterozygosity for a de novo c.3487C-T transition in exon 14 of the ZSWIM6 gene, resulting in an arg1163-to-trp (R1163W) substitution at a highly conserved residue in the SIN3-like domain. In the most mildly affected patient, the mutation was present at a 60:40 ratio of wildtype to mutant allele, suggestive of mosaicism.

In 2 sporadic patients with AFND and the severely affected son of a mildly affected woman, Twigg et al. (2016) identified heterozygosity for the R1163W mutation in the ZSWIM6 gene. Deep sequencing of DNA in 5 tissues from the mildly affected mother confirmed mosaicism for the mutation, with the variant allele being present at approximately 11% in buccal scrapings, 3% in saliva, 2% in urine and blood, and 1% in skin.

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

From University of Washington Center for Mendelian Genomics, University of Washington, SCV000246129.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyesnot providednot providednot providednot providednot providednot providednot provided

From SIB Swiss Institute of Bioinformatics, SCV000803459.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (3)

Description

This variant is interpreted as a Likely Pathogenic, for Acromelic frontonasal dysostosis, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:25105228). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Observed in multiple unrelated patients. (PMID:25105228,26706854).

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

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne - Clinvar_gadteam_Clinical_exome_analysis_3, SCV000803852.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From GenomeConnect, ClinGen, SCV000986913.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedphenotyping onlynot provided

Description

Variant interpretted as pathogenic and reported on 09/20/2018 by GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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

Last Updated: Nov 27, 2021

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