Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000507270 | SCV000604816 | uncertain significance | not specified | 2017-04-07 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002524924 | SCV003741560 | uncertain significance | Inborn genetic diseases | 2022-01-10 | criteria provided, single submitter | clinical testing | The c.7993G>A (p.A2665T) alteration is located in exon 21 (coding exon 21) of the PKD1 gene. This alteration results from a G to A substitution at nucleotide position 7993, causing the alanine (A) at amino acid position 2665 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Department of Pathology and Laboratory Medicine, |
RCV001292147 | SCV001480698 | likely benign | Polycystic kidney disease | no assertion criteria provided | clinical testing | The PKD1 p.Ala2665Thr variant was not identified in the literature nor was it identified in the LOVD 3.0, or PKD1-LOVD databases. The variant was identified in dbSNP (ID: rs764822533) as “With Uncertain significance allele”, ClinVar (as uncertain significance by ARUP), and ADPKD Mutation Database (as likely neutral).The variant was identified in control databases in 46 of 252584 chromosomes at a frequency of 0.000182 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 8 of 20620 chromosomes (freq: 0.000388), European (Non-Finnish) in 35 of 118230 chromosomes (freq: 0.000296), and European (Finnish) in 3 of 15240 chromosomes (freq: 0.000197), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, 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 identified with a co-occurring pathogenic PKD1 variant (p.Leu727Pro), increasing the likelihood that the p.Ala2665Thr variant does not have clinical significance. The p.Ala2665 residue is not conserved in mammals and the variant amino acid Threonine (Thr) is present in rats and mice, increasing the likelihood that this variant does not have clinical significance. In addition, 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 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. |