ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.4057G>A (p.Gly1353Ser)

gnomAD frequency: 0.00001  dbSNP: rs1474271392
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Johns Hopkins Genomics, Johns Hopkins University RCV001250574 SCV001425434 uncertain significance Polycystic kidney disease, adult type 2020-02-20 criteria provided, single submitter clinical testing This PKD1 c.4057G>A has been reported in a patient with clinically diagnosed autosomal dominant polycystic kidney disease. This variant (rs1474271392) is rare (<0.1%) in a large population dataset (gnomAD: 2/247870 total alleles; 0.00081%; no homozygotes) and has not been reported in ClinVar, to our knowledge. PKD1 c.4057G>A is located within the PKD repeat domain, however, the importance of this region is unclear at this time. Three bioinformatic tools queried predict that this substitution would be damaging, and the glycine residue at this position is highly evolutionarily conserved across all species assessed. Due to insufficient evidence that this variant is deleterious, we consider the clinical significance of c.4057G>A to be uncertain at this time.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV001250574 SCV002073232 uncertain significance Polycystic kidney disease, adult type criteria provided, single submitter clinical testing The missense variant p.G1353S in PKD1 (NM_001009944.3) has been previously reported in an individual with ADPKD and classified as Likley Pathogenic by the authors (Carrera P et al,2016). The missense variant c.4057G>A (p.G1353S) in PKD1 (NM_001009944.3) is observed in 1/15916 (0.0063%) alleles from individuals of African background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. The variant has been submitted to ClinVar as Uncertain Significance. The p.G1353S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 1353 of PKD1 is conserved in all mammalian species. The nucleotide c.4057 in PKD1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. In the absence of functional studies and the presence of the variant in only one affected individual, it has been classified as Uncertain Significance
Fulgent Genetics, Fulgent Genetics RCV001250574 SCV002777939 uncertain significance Polycystic kidney disease, adult type 2021-11-01 criteria provided, single submitter clinical testing

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