Submissions for variant NM_018684.4(ZC4H2):c.592C>T (p.Arg198Trp)

dbSNP: rs137962226

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497334	SCV000590081	pathogenic	not provided	2023-06-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33820833, 23623388)
Genomic Medicine Lab, University of California San Francisco	RCV001007949	SCV001167663	likely pathogenic	Wieacker-Wolff syndrome	2019-03-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496910	SCV002808706	likely pathogenic	Wieacker-Wolff syndrome; Wieacker-Wolff syndrome, female-restricted	2022-03-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001007949	SCV003921948	pathogenic	Wieacker-Wolff syndrome	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 5-Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0109 - This gene is known to be associated with X-linked recessive Wieacker-Wolff syndrome (OMIM). However, female pathogenic variant carriers can be affected or unaffected (PMID: 31206972). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan (exon 5). (N) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (P) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Variant is located in a cluster of pathogenic missense variants (Decipher). (P) 0704 - Comparable variant has low previous evidence for pathogenicity. The p.(Arg198Gln) comparable variant has been previously reported in three families with neurogenic arthrogryposis multiplex congenita, in both familial and de novo cases (PMIDs: 23623388; 31206972). (P) 0803 - Low previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic in ClinVar and LOVD. (P) 1007 - No published functional evidence has been identified for this variant. (N) 1203 - Variant shown to be de novo in proband (parental status confirmed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000497334	SCV001809609	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000497334	SCV001954371	likely pathogenic	not provided		no assertion criteria provided	clinical testing