ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.8425G>A (p.Gly2809Arg)

gnomAD frequency: 0.00002  dbSNP: rs398124497
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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) RCV000082584 SCV000114626 uncertain significance not provided 2015-10-27 criteria provided, single submitter clinical testing
Invitae RCV000531951 SCV000629935 pathogenic Autosomal recessive polycystic kidney disease 2023-09-12 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2809 of the PKHD1 protein (p.Gly2809Arg). This variant is present in population databases (rs398124497, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 15805161; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 96434). 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. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002470760 SCV002769192 likely pathogenic Polycystic kidney disease 4 2020-05-01 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a glycine to an arginine (exon 53). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (G8 domain; NCBI, PDB, Decipher) (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0803 - Low previous evidence of pathogenicity in unrelated individuals (ClinVar, Sharp, A., et al. (2005), Chen, H., et al. (2014),) (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
PreventionGenetics, part of Exact Sciences RCV003398682 SCV004119523 pathogenic PKHD1-related disorder 2024-03-01 criteria provided, single submitter clinical testing The PKHD1 c.8425G>A variant is predicted to result in the amino acid substitution p.Gly2809Arg. This variant has been reported in the compound heterozygous state with a pathogenic truncating PKHD1 variant in an individual with autosomal recessive polycystic kidney disease (ARPKD) (Sharp et al. 2005. PubMed ID: 15805161). In addition, at PreventionGenetics, we have previously found this variant with different pathogenic PKHD1 variants in multiple presumably unrelated patients tested for PKD. This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic.
Baylor Genetics RCV002470760 SCV004202277 likely pathogenic Polycystic kidney disease 4 2023-09-25 criteria provided, single submitter clinical testing
Natera, Inc. RCV000531951 SCV001455065 uncertain significance Autosomal recessive polycystic kidney disease 2020-09-16 no assertion criteria provided clinical testing

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