Submissions for variant NM_016580.4(PCDH12):c.922C>T (p.Arg308Ter)

gnomAD frequency: 0.00002  dbSNP: rs370283860

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000760519	SCV000890410	pathogenic	not provided	2023-05-12	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; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000760519	SCV002228448	pathogenic	not provided	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg308*) in the PCDH12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH12 are known to be pathogenic (PMID: 27164683, 29556033). This variant is present in population databases (rs370283860, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with PCDH12-related conditions. ClinVar contains an entry for this variant (Variation ID: 620173). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470971	SCV002769452	pathogenic	Diencephalic-mesencephalic junction dysplasia syndrome 1	2023-07-16	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: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with diencephalic-mesencephalic junction dysplasia syndrome 1 (MIM#251280). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic twice 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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity	RCV002470971	SCV003808689	likely pathogenic	Diencephalic-mesencephalic junction dysplasia syndrome 1	2021-11-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000760519	SCV005436612	pathogenic	not provided	2024-10-01	criteria provided, single submitter	clinical testing	PCDH12: PVS1, PM2, PM3