Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001001040 | SCV001158154 | uncertain significance | Polycystic kidney disease, adult type | 2019-02-01 | criteria provided, single submitter | clinical testing | The PKD1 c.8372G>A; p.Arg2791Gln variant (rs367746233) is reported in the literature in an individual affected with ADPKD; however, it was not demonstrated to be disease-causing (Watnick 1997). This variant is reported as a likely neutral variant in the ADPKD Mutation Database, though the evidence for its classification is not provided. This variant is found in the general population with an overall allele frequency of 0.01% (33/274452 alleles) in the Genome Aggregation Database. The arginine at codon 2791 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the Arg2791Gln variant is uncertain at this time. References: ADPKD Mutation Database: http://pkdb.mayo.edu Watnick TJ et al. An unusual pattern of mutation in the duplicated portion of PKD1 is revealed by use of a novel strategy for mutation detection. Hum Mol Genet. 1997 Sep;6(9):1473-81. |
| Department of Pathology and Laboratory Medicine, |
RCV001354744 | SCV001549432 | likely benign | not provided | no assertion criteria provided | clinical testing | The PKD1 p.Arg2791Gln variant was identified in 1 of 160 proband chromosomes (frequency: 0.00625) from an individual with autosomal dominant polycystic kidney disease and was not identified in 100 control chromosomes from healthy individuals (Watnick_1997_PMID:9285784). The variant was identified in dbSNP (ID: rs367746233) and ClinVar (classified as uncertain significance by ARUP Laboratories by polycystic kidney disease). The variant was identified in control databases in 33 of 274452 chromosomes at a frequency of 0.0001202 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 10 of 30536 chromosomes (freq: 0.000328), Other in 2 of 7010 chromosomes (freq: 0.000285), Latino in 7 of 35190 chromosomes (freq: 0.000199), African in 3 of 22952 chromosomes (freq: 0.000131), Ashkenazi Jewish in 1 of 10114 chromosomes (freq: 0.000099), European (non-Finnish) in 9 of 124260 chromosomes (freq: 0.000072) and European (Finnish) in 1 of 24886 chromosomes (freq: 0.00004), but was not observed in the East Asian population. 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 p.Arg2791 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. Functional evidence from a series of expression constructs with this variant showed no effect on polycystin-1 cleavage, while other amino acid substitutions from different variants almost completely inhibited polycystin-1 cleavage (Qian_2002_PMID:12482949). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. |