Submissions for variant NM_024426.6(WT1):c.193G>A (p.Gly65Arg)

gnomAD frequency: 0.00019  dbSNP: rs374404615

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229513	SCV000290749	benign	Drash syndrome; Frasier syndrome; Wilms tumor 1; 11p partial monosomy syndrome	2024-12-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001104737	SCV001261623	uncertain significance	Wilms tumor 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001105881	SCV001262894	uncertain significance	Nephrotic syndrome, type 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001105882	SCV001262895	uncertain significance	Meacham syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001563568	SCV001786538	likely benign	not provided	2023-07-24	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001563568	SCV002011019	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001820764	SCV002072258	uncertain significance	not specified	2021-01-08	criteria provided, single submitter	clinical testing	This sequence change does not appear to have been previously described in patients with WT1-related disorders and has been described in the gnomAD database with a low population frequency of 0.048% in the non-Finnish European subpopulation (dbSNP rs374404615). The p.Gly65Arg change affects a poorly conserved amino acid residue located in a domain of the WT1 protein that is not known to be functional. The p.Gly65Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly65Arg change remains unknown at this time.
Sema4, Sema4	RCV002257598	SCV002530530	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	curation
Ambry Genetics	RCV002519803	SCV003677616	likely benign	Inborn genetic diseases	2024-08-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001563568	SCV001928534	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001563568	SCV001965702	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739635	SCV005341575	uncertain significance	WT1-related disorder	2024-07-08	no assertion criteria provided	clinical testing	The WT1 c.178G>A variant is predicted to result in the amino acid substitution p.Gly60Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.048% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.