Submissions for variant NM_001009944.3(PKD1):c.11675G>A (p.Arg3892His)

gnomAD frequency: 0.00040  dbSNP: rs748887038

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV001663777	SCV001879416	uncertain significance	not provided	2021-03-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002241573	SCV002511572	uncertain significance	not specified	2022-04-14	criteria provided, single submitter	clinical testing	Variant summary: PKD1 c.11675G>A (p.Arg3892His) results in a non-conservative amino acid change located in the Polycystin cation channel (PKD1/PKD2) domain (IPR013122) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 (54 heterozygotes) in 147232 control chromosomes (gnomAD v3.1, genomes dataset). The high number of heterozygous carriers argues against a fully penetrant autosomal dominant disease association for the variant. The variant, c.11675G>A, has been reported in the literature in at least two adult individuals affected with polycystic kidney disease, however without supportive evidence for causality (Neumann_2013, Audrezet_2016). In addition, the variant was also reported in early onset polycystic kidney disease, together with other variants, therefore the authors of this study proposed hypomorphic role for this variant, with a potential biallelic or digenic inheritance (Durkie_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002495990	SCV002781684	uncertain significance	Polycystic kidney disease, adult type	2022-04-27	criteria provided, single submitter	clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV002495990	SCV005397375	uncertain significance	Polycystic kidney disease, adult type	2023-07-24	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>A) at position 11675 of the coding sequence of the PKD1 gene that results in an arginine to histidine amino acid change at residue 3892 of the PKD1 protein. This is a previously reported variant (ClinVar 1256435) that has been observed as heterozygous or compound heterozygous in individuals with polycystic kidney disease (PMID: 33168999, 26139440, 23300259). This variant is present in 17 of 37712 alleles (0.0451%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this arginine to histidine amino acid change would be damaging, and the Arg3892 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM2, PP3
Mayo Clinic Laboratories, Mayo Clinic	RCV001663777	SCV005411203	uncertain significance	not provided	2024-07-03	criteria provided, single submitter	clinical testing	BS1, PP3, PS4_moderate
PreventionGenetics, part of Exact Sciences	RCV004741053	SCV005344457	uncertain significance	PKD1-related disorder	2024-05-29	no assertion criteria provided	clinical testing	The PKD1 c.11675G>A variant is predicted to result in the amino acid substitution p.Arg3892His. This variant was previously reported in one patient with polycystic kidney disease (PKD), but no functional or genetic studies were performed to help assess the pathogenicity of this variant (Neumann et al. 2013. PubMed ID: 23300259). This variant along with a truncating variant in the PKD2 gene was reported in one case with very early onset PKD; and in the second case with very early onset PKD, this variant was reported in the compound heterozygous state with another PKD1 variant, suggesting this variant could be a hypomorphic allele. By itself, this type of variant may cause no disease or only relatively mild disease. However, in combination with other pathogenic variants, it may contribute to disease severity (Durkie et al. 2021. PubMed ID: 33168999). This variant is reported in 0.096% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.