ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.9619G>A (p.Ala3207Thr)

gnomAD frequency: 0.00001  dbSNP: rs1242089464
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000814732 SCV000955154 pathogenic Autosomal recessive polycystic kidney disease 2024-01-19 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3207 of the PKHD1 protein (p.Ala3207Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of polycystic kidney disease (PMID: 19914852; Invitae). ClinVar contains an entry for this variant (Variation ID: 658007). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV001353367 SCV001548524 likely pathogenic Polycystic kidney disease 4 2021-03-10 criteria provided, single submitter clinical testing This PKHD1 variant (rs1242089464) is rare (<0.1%) in a large population dataset (gnomAD: 1/251034 total alleles; 0.0004%; no homozygotes) and has an entry in ClinVar. It has been observed on the opposite chromosome from other pathogenic variants in individuals affected with PKD4. Three bioinformatics tools queried predict that p.Ala3207Thr would be damaging. The alanine residue at this position is strongly conserved across most vertebrate species assessed. This variant is not predicted to affect normal exon 58 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.9619G>A to be likely pathogenic.
Natera, Inc. RCV000814732 SCV002077941 uncertain significance Autosomal recessive polycystic kidney disease 2021-05-12 no assertion criteria provided clinical testing

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