Submissions for variant NM_001009944.3(PKD1):c.8305C>T (p.Leu2769Phe)

gnomAD frequency: 0.00006  dbSNP: rs771382752

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506044	SCV000604743	likely benign	not specified	2016-10-11	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000506044	SCV000614544	benign	not specified	2017-03-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV004704036	SCV005217048	likely benign	not provided		criteria provided, single submitter	not provided
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000506044	SCV005395814	uncertain significance	not specified	2024-09-17	criteria provided, single submitter	clinical testing	Variant summary: PKD1 c.8305C>T (p.Leu2769Phe) results in a non-conservative amino acid change located in the REJ domain (IPR014010) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 246822 control chromosomes, predominantly at a frequency of 0.0032 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKD1 causing Polycystic Kidney Disease 1 phenotype (0.0005). However, the gnomAD database has noted that pseudogenic regions are not flagged and a 90 bp region surrounding this variant was found to have >95% homology to 4 different loci on chr 16. Therefore population data must be interpreted with caution. c.8305C>T has been reported in the literature in at least 1 individual affected with Polycystic Kidney Disease (example, Kurashige_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Polycystic Kidney Disease 1. Co-occurrences with other pathogenic variant(s) have been reported (PKD2 c.2533C>T, p.Arg845*), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24611717). ClinVar contains an entry for this variant (Variation ID: 440092). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
PreventionGenetics, part of Exact Sciences	RCV003960197	SCV004780590	likely benign	PKD1-related disorder	2023-02-13	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).