rs369626030
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_138694.4(PKHD1):āc.6097A>Gā(p.Arg2033Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.6097A>G | p.Arg2033Gly | missense_variant | 37/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.6097A>G | p.Arg2033Gly | missense_variant | 37/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.6097A>G | p.Arg2033Gly | missense_variant | 37/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251288Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135792
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461030Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 726854
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74364
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2033 of the PKHD1 protein (p.Arg2033Gly). This variant is present in population databases (rs369626030, gnomAD 0.01%). This missense change has been observed in individuals with polycystic kidney disease (PMID: 16523049, 20413436, 30366773). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 554925). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 08, 2017 | - - |
Polycystic kidney disease 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 05, 2021 | Variant summary: PKHD1 c.6097A>G (p.Arg2033Gly) results in a non-conservative amino acid change located in the G8 domain (IPR019316) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251288 control chromosomes. c.6097A>G has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (example, Adeya_2006, Gunay-Aygun_2010, LingChen_2019). One of these reports described this variant in a compound heterozygous genotype with p.Q3392X in a family with two sibs, one of whom was reportedly unaffected with diffuse low attenuation in the liver consistent with fatty infiltration while the other had congenital hepatic fibrosis and renal enlargement but no evidence of kidney dysfunction or hypersplenism (Adeva_2006). The authors reported this as a "mild mutation" in patients with a predominant biliary phenotype. Another report described the variant in a compound heterozygous genotype with p.Ile2957Thr in two non-perinatal onset cases from a family (Gunay-Aygun_2010). Finally, the third ascertained report in the context of this evaluation describes this variant in compound heterozygosity with p.Arg3772Ter in a patient with polycystic liver/kidney disease who underwent an NGS panel for 42 known disease causing genes associated with jaundice or cholestasis and 10 pathway related genes (Ling Chen_2019). These data indicate that the variant maybe associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance citing overlapping evidence cited here. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until additional clinical reports and functional evidence are identified. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at