Submissions for variant NM_001009944.3(PKD1):c.3490G>A (p.Gly1164Arg)

dbSNP: rs2151801188

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Fulgent Genetics, Fulgent Genetics	RCV001536082	SCV001752783	likely pathogenic	Polycystic kidney disease, adult type	2022-01-31	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV003481121	SCV004226899	likely pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing	PP3, PM2, PS4_moderate
GeneDx	RCV003481121	SCV005081249	uncertain significance	not provided	2023-10-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27782177)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001536082	SCV005398865	likely pathogenic	Polycystic kidney disease, adult type	2024-10-09	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) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated PKD domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been been classified as likely pathogenic by clinical laboratories on ClinVar, as well as a VUS entry. This variant has also been observed in multiple unrelated individuals with polycystic kidney disease (PMID: 38541974, 35778421, 26453610, 32457805, 32398770, 27782177). (SP) 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
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001536082	SCV006052524	uncertain significance	Polycystic kidney disease, adult type	2023-10-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003908887	SCV004725852	uncertain significance	PKD1-related disorder	2023-12-14	no assertion criteria provided	clinical testing	The PKD1 c.3490G>A variant is predicted to result in the amino acid substitution p.Gly1164Arg. This variant was reported in an individual with autosomal dominant polycystic kidney disease (Table S2, Jin et al. 2016. PubMed ID: 27782177). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Alternative variant at the same nucleotide c.3490G>C leading to the same protein change p.Gly1164Arg was reported in an individual with autosomal dominant polycystic kidney disease (Table S3, Hwang et al. 2016. PubMed ID: 26453610). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.