Submissions for variant NM_021964.3(ZNF148):c.1624C>T (p.Gln542Ter)

dbSNP: rs2107831036

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001754574	SCV001994825	likely pathogenic	Global developmental delay, absent or hypoplastic corpus callosum, and dysmorphic facies	2021-10-08	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001754574	SCV005399732	pathogenic	Global developmental delay, absent or hypoplastic corpus callosum, and dysmorphic facies	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Only variants predicted to result in truncated proteins have been reported and no functional studies have been performed to assess the disease mechanism (PMIDs: 27964749, 36444493). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. A variable phenotype has been observed in affected individuals (PMID: 27964749, OMIM). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the affected serine-rich/PEST domain (PMID: 27964749). (I) 0702 - Other truncating variants comparable to the one identified in this case have strong previous evidence for pathogenicity. There are four downstream truncating variants reported as either likely pathogenic or pathogenic (ClinVar, DECIPHER). A fifth truncating variant has also been reported as de novo in an individual with microcephaly, developmental delay, short stature and decreased body weight (GeneDx personal correspondence). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported once as likely pathogenic in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV004815620	SCV005439823	pathogenic	not provided	2024-06-22	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation as the last 253 amino acids are lost; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27964749, 37035737)