Submissions for variant NM_001009944.3(PKD1):c.5995G>A (p.Gly1999Ser)

dbSNP: rs2092437527

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253576	SCV001429366	likely pathogenic	Polycystic kidney disease, adult type	2019-08-15	criteria provided, single submitter	clinical testing
GeneDx	RCV001548196	SCV001768063	uncertain significance	not provided	2021-05-24	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22383692, 17582161, 24694054)
University of Iowa Renal Genetics Clinic, University of Iowa	RCV001253576	SCV003804385	likely pathogenic	Polycystic kidney disease, adult type	2023-01-31	criteria provided, single submitter	clinical testing	ACMG pathogenicity criteria PM2, PP1, PP3, PP5. This variant has been previously described in two patients with autosomal dominant polycystic kidney disease (Rossetti, S., et al, J Am Soc Nephrol. 2012 May;23(5):915-33 and Rossetti, S., et al, J Am Soc Nephrol. 2007 Jul;18(7):2143-60) and also segregating in three affected family members (Obeidova, L., et al, BMC Med Genet. 2014 Apr 3;15:41). This variant has not been reported by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/); it is predicted to be pathogenic by 5 of 6 pathogenicity methods (PhyloP, SIFT, LRT, Polyphen HDIV, Mutation Taster, and GERP). We have identified this variant within two affected individuals with PKD who are fourth-degree relatives and also have a significant family history of intracranial aneurysms.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001253576	SCV004809707	pathogenic	Polycystic kidney disease, adult type	2024-04-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001253576	SCV005039074	likely pathogenic	Polycystic kidney disease, adult type	2024-03-26	criteria provided, single submitter	clinical testing	Variant summary: PKD1 c.5995G>A (p.Gly1999Ser) results in a non-conservative amino acid change located in the PKD domain (IPR000601) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 240098 control chromosomes (gnomAD). c.5995G>A has been reported in the literature in multiple individuals affected with Polycystic Kidney Disease 1 and has been found to segregate with disease in at least one family (e.g. Rossetti_2007, Obeidova_2014, Kurashige_2015, Yu_2022, Lindemann_2023). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24611717, 36938073, 24694054, 17582161, 35778421). ClinVar contains an entry for this variant (Variation ID: 976316). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001253576	SCV005087064	pathogenic	Polycystic kidney disease, adult type	2023-12-21	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 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) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated PKD domain (DECIPHER). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The variants p.(Gly1999Val) and p.(Gly1999Ala) have been classified as likely pathogenic (pkdb, PMID: 17582161). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by clinical laboratories in ClinVar, and has been observed in multiple families with polycystic kidney disease (PMIDs: 17582161, 35778421, 24694054, VCGS laboratory). This variant has also been classified once as a VUS in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign