Submissions for variant NM_001009944.3(PKD1):c.8299C>T (p.Arg2767Cys)

dbSNP: rs2092203712

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001091875	SCV001248135	pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV001095580	SCV001251213	likely pathogenic	Polycystic kidney disease, adult type	2020-02-05	criteria provided, single submitter	research	PM1, PM2, PP3, PP4, PP5
GeneDx	RCV001091875	SCV001802385	likely pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as R2767C could disrupt the protein cleavage that is critical for the protein's function (PMID: 17574468); 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: 23431072, 17574468, 22508176, 31317121, 33454723)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001095580	SCV002767391	pathogenic	Polycystic kidney disease, adult type	2021-05-06	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 arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 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 REJ domain (PMID: 17574468). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. A different variant in the same codon resulting in a change to a proline has been shown to cause autosomal dominant polycystic kidney disease (ADPKD) (PMID: 22508176). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in individuals with ADPKD (ClinVar, PMID: 17574468, 22508176). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies using transfected cells show that this variant disrupts polycyctin-1 cleavage (PMID: 17574468). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics, University of Leipzig Medical Center	RCV001095580	SCV004027771	likely pathogenic	Polycystic kidney disease, adult type	2023-05-12	criteria provided, single submitter	clinical testing	Criteria applied: PM5_STR,PS4_MOD,PM1,PM2_SUP
Mayo Clinic Laboratories, Mayo Clinic	RCV001091875	SCV005414319	likely pathogenic	not provided	2024-01-03	criteria provided, single submitter	clinical testing	PM1, PM2, PS3_supporting, PS4
Fulgent Genetics, Fulgent Genetics	RCV001095580	SCV005645125	pathogenic	Polycystic kidney disease, adult type	2024-04-29	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292112	SCV001480944	pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Arg2767Cys variant was identified in 4 of 1564 proband chromosomes (frequency: 0.003) from individuals or families with ADPKD (Audrezet 2012, Garcia-Gonzalez 2007). The variant was also identified in ADPKD Mutation Database (with highly likely pathogenic classification), database. The variant was identified by our laboratory in 1 individual with PKD in a family with this variant segregating in 2 individuals with the disease. The variant was not identified in dbSNP, ClinVar, Genesight-COGR, LOVD 3.0, PKD1-LOVD, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Arg2767 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Egg jelly receptor, REJ-like functional domain(s) increasing the likelihood that it may have clinical significance. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.