Submissions for variant NM_001009944.3(PKD1):c.6878C>T (p.Pro2293Leu)

gnomAD frequency: 0.00006  dbSNP: rs530832015

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000989453	SCV001139783	benign	Polycystic kidney disease, adult type	2019-05-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000989453	SCV002767112	uncertain significance	Polycystic kidney disease, adult type	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease predominantly caused by monoallelic variants, with rare reports of bi-allelic variants causing disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a proline to a leucine (exon 15). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (33 heterozygotes, 0 homozygotes). (P) 0504 - Same amino acid change has been observed in mammals. (B) 0600 - Variant is located in an annotated domain or motif (REJ domain; UniProt). (N) 0704 - Comparable variant has low previous evidence for pathogenicity. An alternate missense variant at the same residue (p.Pro2293Ser) has been reported pathogenic in an individual with multiple renal cysts (ClinVar). (P) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported as likely benign in an individual with PKD that also had a second pathogenic variant (PKD mutation database, PMID: 30333007). In addition, this variant has been reported as disease modifying (PMID: 25263802). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
PreventionGenetics, part of Exact Sciences	RCV003953397	SCV004782212	likely benign	PKD1-related disorder	2022-05-20	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).