Submissions for variant NM_001009944.3(PKD1):c.7489+5G>A

dbSNP: rs2092337963

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV003229568	SCV001430288	likely pathogenic	Autosomal dominant polycystic kidney disease	2022-11-20	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004594256	SCV005086306	likely pathogenic	Polycystic kidney disease, adult type	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic: Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 1 (MIM#173900). (I) 0107 - This gene is associated with autosomal dominant disease. Polycystic kidney disease 1 (MIM#173900) is predominantly caused by monoallelic variants, with rare reports of biallelic variants causing disease (OMIM). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR studies showed abnormal splicing of intron 18 in the sample from this individual, consistent with a retention of 93 base pairs of intron 18 which is predicted to result in nonsense-mediated decay (NMD) (unpublished research data from Garvan Institute of Medical Research). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable splice site variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS in an individual with typical ADPKD (PMID: 33437033, ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1207 - Parental origin of the variant is unresolved. Analysis by a research laboratory has shown that this variant is not maternally inherited; however, a sample from this individual's father has not been tested (Garvan Institute of Medical Research). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV004594256	SCV005638324	pathogenic	Polycystic kidney disease, adult type	2024-02-14	criteria provided, single submitter	clinical testing
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001249110	SCV001422330	uncertain significance	not provided	2019-01-01	flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003963153	SCV004784526	uncertain significance	PKD1-related disorder	2023-11-10	no assertion criteria provided	clinical testing	The PKD1 c.7489+5G>A variant is predicted to interfere with splicing. This variant has been reported in an individual with polycystic kidney disease (Table S3, Pt D158, Mallawaarachchi et al. 2021. PubMed ID: 33437033). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.