ClinVar

Description

The PKD1 p.Arg3672Gln variant was not identified in the literature nor was it identified in the PKD1-LOVD. The variant was identified in dbSNP (ID: rs201220835) as "With other allele", ClinVar (classified as likely benign by ARUP; as uncertain significance by Athena Diagnostics), LOVD 3.0, and ADPKD Mutation Database (as likely neutral). The variant was also identified in our laboratory with a co-occurring pathogenic PKD1 variant (PKD1 c.5510G>A (p.Trp1837X)), increasing the likelihood that the p.Arg3672Gln variant does not have clinical significance. The variant was identified in control databases in 108 of 249596 chromosomes (2 homozygous) at a frequency of 0.0004 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 4 of 21718 chromosomes (freq: 0.0002), Other in 2 of 5944 chromosomes (freq: 0.0003), Latino in 6 of 32178 chromosomes (freq: 0.0002), European in 83 of 112264 chromosomes (freq: 0.000739), EastAsian in 1 of 17524 chromosomes (freq: 0.000057), and South Asian in 12 of 27884 chromosomes (freq: 0.0004), while the variant was not observed in the Ashkenazi Jewish, and Finnish, populations. The p.Arg3672 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 c.11015G>A variant occurs in the last three bases 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, 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% 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.