ClinVar Genomic variation as it relates to human health

NM_138694.3(PKHD1):c.9107T>G(V3036G) is a missense variant classified as likely pathogenic in the context of autosomal recessive polycystic kidney disease, PKHD1-related. V3036G has been observed in cases with relevant disease (PMID: 27225849, 33532864, 33940108, 12874454, No PMID_Guomin_2017). Functional assessments of this variant are not available in the literature. V3036G has been observed in population frequency databases (gnomAD: OTH 0.02%). In summary, NM_138694.3(PKHD1):c.9107T>G(V3036G) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

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 valine to glycine (exon 58). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (8 heterozygotes, 0 homozygotes). (P) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD; p.(Val3036Ile) (1 heterozygote, 0 homozygotes), p.(Val3036Leu) (2 heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and low conservation. (N) 0600 - Variant is located in an annotated domain or motif (right handed beta helix region; NCBI, PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0803 - Low previous evidence of pathogenicity in unrelated individuals. This variant has been reported in individuals with ARPKD (PMIDs: 27225849, 15805161). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1102 - Strong phenotype match. (P) 1201 - Heterozygous variant detected in trans with a second (at least likely) pathogenic heterozygous variant in a recessive disease. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) – Benign

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 3036 of the PKHD1 protein (p.Val3036Gly). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 27225849, 33123899, 33532864, 33940108). 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: 594333). 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. For these reasons, this variant has been classified as Pathogenic.

Variant summary: PKHD1 c.9107T>G (p.Val3036Gly) results in a non-conservative amino acid change located in the Right handed beta helix domain (IPR039448) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250770 control chromosomes. c.9107T>G has been reported in the literature in multiple individuals affected with Autosomal Recessive Polycystic Kidney (example, Domingo-Gallego_2021, Furu_2003, Ishiko_2022, Melchionda_2016, Rao_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33532864, 12874454, 34536170, 27225849, 31328266). ClinVar contains an entry for this variant (Variation ID: 594333. Pathogenic/Likely pathogenic, n=5; VUS, n=2). Based on the evidence outlined above, the variant was classified as pathogenic.