Submissions for variant NM_001009944.3(PKD1):c.7937T>C (p.Ile2646Thr)

gnomAD frequency: 0.00029  dbSNP: rs374500158

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197009	SCV001367644	uncertain significance	Polycystic kidney disease, adult type	2018-12-03	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,PP5.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001197009	SCV002768579	likely benign	Polycystic kidney disease, adult type	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely Benign. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from an isoleucine to a threonine (exon 21). (N) 0251 - Variant is heterozygous. (N) 0308 - Population frequency for this variant is out of keeping with known incidence of polycystic kidney disease (gnomAD (v2): 65 heterozygotes, 0 homozygotes). (B) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygotes). (N) 0502 - Missense variant with conflicting in-silico predictions and uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (REJ domain (Hoefele, J. et al. (2011))). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0803 - Low previous evidence of pathogenicity in unrelated individuals (Hoefele, J. et al. (2011)). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
GeneDx	RCV003328657	SCV004035565	uncertain significance	not provided	2023-09-11	criteria provided, single submitter	clinical testing	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: 21115670)
CeGaT Center for Human Genetics Tuebingen	RCV003328657	SCV004142850	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	PKD1: BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292021	SCV001480619	uncertain significance	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Ile2646Thr variant was identified in 1 of 186 proband chromosomes (frequency: 0.005) from German individuals or families with ADPKD (Hoefele_2011_ 21115670). The variant was also identified in dbSNP (ID: rs374500158) as “NA”, ADPKD Mutation Database (classified indeterminate), and in control databases in 60 of 258388 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 2 of 6236 chromosomes (freq: 0.0003), Latino in 4 of 34178 chromosomes (freq: 0.0001), European Non-Finnish in 52 of 121050 chromosomes (freq: 0.0004), Ashkenazi Jewish in 1 of 9890 chromosomes (freq: 0.0001), and European Finnish in 1 of 15996 chromosomes (freq: 0.00006), while not observed in the African, East Asian, and South Asian populations. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant was not identified in ClinVar, GeneInsight-COGR, LOVD 3.0, and PKD1-LOVD databases. Although the p.Ile2646 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Ile variant may impact the protein. 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.