Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001384432 | SCV001583928 | pathogenic | not provided | 2017-07-06 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change is unable to rescue the phenotype in a zebrafish knockout model (PMID: 26056227). This variant has been reported to segregate with disease in two families affected with arthrogryposis multiplex congenita and intellectual disability (PMID: 23623388) and another family affected with intellectual disability, contractures, and spasticity (PMID: 26056227). ClinVar contains an entry for this variant (Variation ID: 50983). This sequence change replaces arginine with tryptophan at codon 213 of the ZC4H2 protein (p.Arg213Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. |
| Gene |
RCV001384432 | SCV002074112 | pathogenic | not provided | 2021-12-10 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23623388, 26056227, 28345801, 29150902, 33504798, 33739554, 31206972) |
| Ambry Genetics | RCV002354226 | SCV002655406 | pathogenic | Inborn genetic diseases | 2022-01-25 | criteria provided, single submitter | clinical testing | The p.R213W variant (also known as c.637C>T), located in coding exon 5 of the ZC4H2 gene, results from a C to T substitution at nucleotide position 637. The arginine at codon 213 is replaced by tryptophan, an amino acid with dissimilar properties. This variant co-segregated in multiple families in individuals with ZC4H2-related disorder (Hirata H et al. Am. J. Hum. Genet., 2013 May;92:681-95; May M et al. Hum. Mol. Genet., 2015 Sep;24:4848-61; Hu H et al. Mol. Psychiatry, 2016 Jan;21:133-48). This variant has been determined to be the result of a de novo mutation or germline mosaicism in an individual with ZC4H2-related disorder (Frints SGM et al. Hum Mutat, 2019 12;40:2270-2285). In addition, this variant was detected in the hemizygous state in a male patient with club feet, developmental delay, spasticity, seizure and no other potentially causative variants; the variant was maternally inherited (Ambry internal data). This alteration is predicted to disrupt the nuclear localization signal motif (Ambry internal data; Hirata H et al. Am. J. Hum. Genet., 2013 May;92:681-95; May M et al. Hum. Mol. Genet., 2015 Sep;24:4848-61), and has been determined to impact protein function (Hirata H et al. Am. J. Hum. Genet., 2013 May;92:681-95; May M et al. Hum. Mol. Genet., 2015 Sep;24:4848-61; Ma P et al. Open Biol, 2017 08;7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| OMIM | RCV000043679 | SCV000071690 | pathogenic | Wieacker-Wolff syndrome | 2013-05-02 | no assertion criteria provided | literature only |