ClinVar Genomic variation as it relates to human health
NM_018684.4(ZC4H2):c.199C>T (p.Arg67Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_018684.4(ZC4H2):c.199C>T (p.Arg67Ter)
Variation ID: 429826 Accession: VCV000429826.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xq11.2 X: 64921843 (GRCh38) [ NCBI UCSC ] X: 64141723 (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 Jul 2, 2017 Jun 24, 2023 Jun 12, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_018684.4:c.199C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_061154.1:p.Arg67Ter nonsense NM_001178032.3:c.130C>T NP_001171503.1:p.Arg44Ter nonsense NM_001178033.3:c.199C>T NP_001171504.1:p.Arg67Ter nonsense NM_001243804.2:c.130C>T NP_001230733.1:p.Arg44Ter nonsense NR_045044.2:n.527C>T non-coding transcript variant NC_000023.11:g.64921843G>A NC_000023.10:g.64141723G>A NG_021200.2:g.117902C>T - Protein change
- R67*, R44*
- Other names
- NM_018684.4(ZC4H2):c.199C>T
- p.Arg67Ter
- Canonical SPDI
- NC_000023.11:64921842:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
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 | ||
---|---|---|---|---|---|---|
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. |
|||
ZC4H2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
164 | 292 |
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. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 12, 2023 | RCV000494211.5 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 28, 2019 | RCV000763627.3 | |
Pathogenic (1) |
criteria provided, single submitter
|
Sep 6, 2018 | RCV001265964.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 24, 2023 | RCV002527090.3 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Apr 13, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000611017.1
First in ClinVar: Jul 02, 2017 Last updated: Jul 02, 2017 |
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Wieacker-Wolff syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894495.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
Likely pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Wieacker-Wolff syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001141895.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
Pathogenic
(Sep 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001444136.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
CNS hypomyelination (present) , Clonus (present) , Laryngomalacia (present) , Duane anomaly (present) , Central hypotonia (present) , Developmental dysplasia of the hip (present) , … (more)
CNS hypomyelination (present) , Clonus (present) , Laryngomalacia (present) , Duane anomaly (present) , Central hypotonia (present) , Developmental dysplasia of the hip (present) , Areflexia (present) , Coarse facial features (present) , Ptosis (present) , Micrognathia (present) , Scoliosis (present) , Global developmental delay (present) , Short stature (present) , Arthrogryposis multiplex congenita (present) , Muscular hypotonia (present) , Hearing impairment (present) (less)
Sex: female
Ethnicity/Population group: Hispanic
|
|
Pathogenic
(Jan 24, 2023)
|
criteria provided, single submitter
Method: curation
|
Wieacker-Wolff syndrome, female-restricted
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761210.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The heterozygous p.Arg67Ter variant in ZC4H2 was identified by our study in one individual with female-restricted Wieacker-Wolff syndrome. Trio exome analysis showed this variant to … (more)
The heterozygous p.Arg67Ter variant in ZC4H2 was identified by our study in one individual with female-restricted Wieacker-Wolff syndrome. Trio exome analysis showed this variant to be de novo. The p.Arg67Ter variant in ZC4H2 has been previously reported in two individuals with Wieacker-Wolff syndrome (PMID: 31206972; PMID: 31885220). This variant was found to be de novo in two individuals with confirmed paternity and maternity (PMID: 31206972; PMID: 31885220). This variant was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 429826) and has been interpreted as pathogenic by GeneDx, Fulgent Genetics, and Ambry Genetics and as likely pathogenic by Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics and Mendelics. In vitro functional studies provide some evidence that the p.Arg67Ter variant may impact protein function (PMID: 31885220). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 67, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the ZC4H2 gene is an established disease mechanism in female-restricted Wieacker-Wolff syndrome. In summary, this variant meets criteria to be classified as pathogenic for female-restricted Wieacker-Wolff syndrome. ACMG/AMP Criteria applied: PVS1, PS2, PS3_Supporting, PS4_Supporting, PM2_Supporting (Richards 2015). (less)
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Wieacker-Wolff syndrome, female-restricted
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Lifecell International Pvt. Ltd
Accession: SCV003925690.1
First in ClinVar: May 27, 2023 Last updated: May 27, 2023 |
Comment:
A Heterozygous Nonsense variant c.199C>T in Exon 2 of the ZC4H2 gene that results in the amino acid substitution p.Arg67* was identified. The observed variant … (more)
A Heterozygous Nonsense variant c.199C>T in Exon 2 of the ZC4H2 gene that results in the amino acid substitution p.Arg67* was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/ Likely Pathogenic [Variation ID:429826]. The observed variant has been previously reported in patients affected with arthrogryposis multiplex congenita (Frints, Suzanna G M et al., 2019). For these reasons, this variant has been classified as Pathogenic. (less)
Ethnicity/Population group: Asian
Geographic origin: India
|
|
Pathogenic
(Jun 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000582490.4
First in ClinVar: Jul 02, 2017 Last updated: Jun 24, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: a truncated protein with altered subcellular localization (Wang et al., 2020); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31349857, 31885220, 33949289, 36250278, 31206972) (less)
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita. | Frints SGM | Human mutation | 2019 | PMID: 31206972 |
Text-mined citations for rs1131691616 ...
HelpRecord last updated Mar 30, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.