ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.2936C>T (p.Thr979Ile)

gnomAD frequency: 0.00001  dbSNP: rs747895516
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668499 SCV000793114 uncertain significance Autosomal recessive polycystic kidney disease 2017-07-27 criteria provided, single submitter clinical testing
Baylor Genetics RCV000668499 SCV001163052 pathogenic Autosomal recessive polycystic kidney disease criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000668499 SCV001427113 likely pathogenic Autosomal recessive polycystic kidney disease 2018-06-21 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_138694.3(PKHD1):c.2936C>T, has been identified in exon 27 of 67 of the PKHD1 gene. The variant is predicted to result in a moderate amino acid change from threonine to isoleucine at position 979 of the protein (NP_619639.3(PKHD1):p.(Thr979Ile)). The threonine residue at this position has low conservation (100 vertebrates, UCSC), and is located within the IPT/TIG domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.001% (4/245860 heterozygotes and 0 homozygote). The variant has previously been described as pathogenic in patients with polycystic kidney disease, where a second variant in trans has also been identified (Losekoot M. et al. (2005), Adeva M. et al. (2006)). Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with polycystic kidney disease.
Invitae RCV000668499 SCV002205733 pathogenic Autosomal recessive polycystic kidney disease 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 979 of the PKHD1 protein (p.Thr979Ile). This variant is present in population databases (rs747895516, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive polycystic kidney disease (PMID: 16133180, 16523049, 32939031). ClinVar contains an entry for this variant (Variation ID: 553118). 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%. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003459597 SCV004204644 pathogenic Polycystic kidney disease 4 2023-06-01 criteria provided, single submitter clinical testing

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