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NM_018684.4(ZC4H2):c.535_538dup (p.Arg180fs) AND Wieacker-Wolff syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 16, 2020
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001267690.3

Allele description [Variation Report for NM_018684.4(ZC4H2):c.535_538dup (p.Arg180fs)]

NM_018684.4(ZC4H2):c.535_538dup (p.Arg180fs)

Gene:
ZC4H2:zinc finger C4H2-type containing [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
Xq11.2
Genomic location:
Preferred name:
NM_018684.4(ZC4H2):c.535_538dup (p.Arg180fs)
HGVS:
  • NC_000023.11:g.64919065_64919068dup
  • NG_021200.2:g.120677_120680dup
  • NM_001178032.3:c.466_469dup
  • NM_001178033.3:c.398+1013_398+1016dup
  • NM_001243804.2:c.466_469dup
  • NM_018684.4:c.535_538dupMANE SELECT
  • NP_001171503.1:p.Arg157fs
  • NP_001230733.1:p.Arg157fs
  • NP_061154.1:p.Arg180fs
  • NC_000023.10:g.64138945_64138948dup
  • NR_045044.2:n.863_866dup
Protein change:
R157fs
Links:
dbSNP: rs1929057804
NCBI 1000 Genomes Browser:
rs1929057804
Molecular consequence:
  • NM_001178032.3:c.466_469dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001243804.2:c.466_469dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_018684.4:c.535_538dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001178033.3:c.398+1013_398+1016dup - intron variant - [Sequence Ontology: SO:0001627]
  • NR_045044.2:n.863_866dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Wieacker-Wolff syndrome
Synonyms:
Wieacker syndrome; Contractures of feet, muscle atrophy, and oculomotor apraxia; Apraxia, oculomotor, with congenital contractures and muscle atrophy; See all synonyms [MedGen]
Identifiers:
Gene: 4183; MONDO: MONDO:0010758; MedGen: C0796200; Orphanet: 3454; Orphanet: 85283; OMIM: 314580

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001445937Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
no assertion criteria provided
Likely pathogenic
(Nov 16, 2020) 		germlinecuration

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001445937.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The hemizygous p.Arg180IlefsTer46 variant in ZC4H2 was identified by our study in 1 individual with Wieacker-Wolff syndrome. Trio genome analysis showed this variant to be de novo. The variant has not been previously reported in individuals with Wieacker-Wolff syndrome and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 180 and leads to a premature termination codon 46 amino acids downstream. This termination codon occurs the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. While there is some evidence to suggest that hemizygous loss of function of the ZC4H2 gene is a disease mechanism in Wieacker-Wolff syndrome, this association is not yet strongly established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for X-linked Wieacker-Wolff syndrome. ACMG/AMP Criteria applied: PS2, PM2, PVS1_supporting (Richards 2015).

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

Last Updated: Jun 23, 2024