Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Department of Pathology and Laboratory Medicine, |
RCV001292327 | SCV001481108 | uncertain significance | Polycystic kidney disease | no assertion criteria provided | clinical testing | The PKHD1 p.Gln3770Arg variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, GeneInsight-COGR, LOVD 3.0, databases. The variant was only identified in RWTH AAachen University ARPKD database. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Gln3770 residue is not conserved in mammals and four out of five 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 p.Gln3770Arg variant occurs in the second last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. The identification of this homozygous variant in an individual with apparent ARPKD increases the likelihood it may have clinical significance. 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 uncertain significance. |