Submissions for variant NM_018684.4(ZC4H2):c.199C>T (p.Arg67Ter)

dbSNP: rs1131691616

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494211	SCV000582490	pathogenic	not provided	2023-06-12	criteria provided, single submitter	clinical testing	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)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000494211	SCV000611017	likely pathogenic	not provided	2017-04-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763627	SCV000894495	pathogenic	Wieacker-Wolff syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000763627	SCV001141895	likely pathogenic	Wieacker-Wolff syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001265964	SCV001444136	pathogenic	Inborn genetic diseases	2018-09-06	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002527090	SCV003761210	pathogenic	Wieacker-Wolff syndrome, female-restricted	2023-01-24	criteria provided, single submitter	curation	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).
Lifecell International Pvt. Ltd	RCV002527090	SCV003925690	pathogenic	Wieacker-Wolff syndrome, female-restricted		criteria provided, single submitter	clinical testing	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.