ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.8411T>A (p.Met2804Lys)

gnomAD frequency: 0.00001  dbSNP: rs794727759
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000790749 SCV000332131 likely pathogenic not provided 2015-07-21 criteria provided, single submitter clinical testing
Counsyl RCV000336528 SCV000800516 uncertain significance Autosomal recessive polycystic kidney disease 2017-04-12 criteria provided, single submitter clinical testing
Laboratory of Molecular Genetics, Children's Memorial Health Institute RCV000336528 SCV001434257 likely pathogenic Autosomal recessive polycystic kidney disease 2020-05-12 criteria provided, single submitter clinical testing
Invitae RCV000336528 SCV001574613 likely pathogenic Autosomal recessive polycystic kidney disease 2023-10-16 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 2804 of the PKHD1 protein (p.Met2804Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 20413436, 27752906). ClinVar contains an entry for this variant (Variation ID: 197958). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PKHD1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics RCV003474935 SCV004202222 likely pathogenic Polycystic kidney disease 4 2023-10-22 criteria provided, single submitter clinical testing
Sydney Genome Diagnostics, Children's Hospital Westmead RCV000336528 SCV001449398 likely pathogenic Autosomal recessive polycystic kidney disease 2018-04-20 no assertion criteria provided clinical testing this individual was heterozygous for the c.8411T>A variant in the PKHD1 gene. The variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP). It is listed in ClinVar as a likely pathogenic variant, without any supporting evidence provided. In silico analysis of pathogenicity (through Alamut Visual v2.8.1) is inconclusive regarding this change; SIFT predicts it to be likely pathogenic whereas PolyPhen2 and MutationTaster predicts this variant to be benign. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines. Testing of parental specimens (see reports MG-18-02570 & MG-18-02571) indicates that two PKHD1 variants are in trans (on separate alleles). In light of this finding, the c.8411T>A variant has been reclassified as likely pathogenic, according to ACMG guidelines.

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