Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001000810 | SCV001157873 | uncertain significance | Polycystic kidney disease, adult type | 2018-09-11 | criteria provided, single submitter | clinical testing | The PKD1 c.3344C>T; p.Thr1115Met variant (rs552292318) has been described in at least one individual with autosomal dominant polycystic kidney disease (ADPKD; Jin 2016). Although these authors suggested it is likely pathogenic, they don't provide criteria for variant classification. It is observed in the South Asian population at an overall frequency of 0.23% (70/30734 alleles) in the Genome Aggregation Database. The threonine at codon 1115 is moderately conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. However, due to limited clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty. References: Jin M et al. System analysis of gene mutations and clinical phenotype in Chinese patients with autosomal-dominant polycystic kidney disease. Sci Rep. 2016 Oct 26;6:35945. |
| Athena Diagnostics Inc | RCV001664606 | SCV001879429 | likely benign | not specified | 2021-01-19 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV001355071 | SCV001549839 | likely benign | Bile duct cancer | no assertion criteria provided | clinical testing | The PKD1 p.Thr1115Met variant was not identified in the literature nor was it identified in the ClinVar, LOVD 3.0, ADPKD Mutation Database, or PKD1-LOVD databases. The variant was identified in dbSNP (ID: rs552292318). The variant was identified in control databases in 77 of 241370 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 70 of 30734 chromosomes (freq: 0.002), Other in 1 of 5402 chromosomes (freq: 0.0002), Latino in 2 of 33500 chromosomes (freq: 0.00006), and European in 4 of 107734 chromosomes (freq: 0.00004); it was not observed in the African, Ashkenazi Jewish, East Asian, or Finnish populations. The variant was identified in our laboratory with a co-occurring pathogenic PKD1 variant (c.12682dupC, p.Arg4228Profs*157), increasing the likelihood that the p.Thr1115Met variant does not have clinical significance. The p.Thr1115 residue is conserved in mammals but not in more distantly related organisms, and 5 of 5 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) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. |