rs376040501
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_138694.4(PKHD1):c.1123C>T(p.Arg375Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000259 in 1,583,548 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R375Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.1123C>T | p.Arg375Trp | missense_variant | 15/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.1123C>T | p.Arg375Trp | missense_variant | 15/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.1123C>T | p.Arg375Trp | missense_variant | 15/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251092Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135706
GnomAD4 exome AF: 0.0000252 AC: 36AN: 1431342Hom.: 0 Cov.: 27 AF XY: 0.0000350 AC XY: 25AN XY: 713984
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74362
ClinVar
Submissions by phenotype
Polycystic kidney disease 4 Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 04, 2020 | - - |
Likely pathogenic, no assertion criteria provided | research | Genomics And Bioinformatics Analysis Resource, Columbia University | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.66; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000528296). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 27225849). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 24, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center | Feb 24, 2020 | The c.1123C>T variant is a heterozygous single base pair substitution at nucleotide 1123 in exon 15 of 67 of the PKHD1 gene, resulting in the substitution of a well-conserved, positively charged, Arginine residue at amino acid position 375 to a non-polar Tryptophan residue. The c.1123C>T variant is observed in the Genome Aggregation Database (gnomAD) in heterozygous but not homozygous form indicating it is not a common benign variant in the populations represented in this database. This variant has been observed in trans with a pathogenic variant in individuals with AR Polycystic Kidney Disease (PMID: 16133180, 30595564, 27225849). This variant is classified as likely pathogenic. - |
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 10, 2022 | PP4, PM2, PM3_strong, PS4_moderate - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 07, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30586318, 19940839, 31730820, 27225849, 16133180, 33123899) - |
Likely pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Autosomal recessive polycystic kidney disease Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 375 of the PKHD1 protein (p.Arg375Trp). This variant is present in population databases (rs376040501, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 16133180, 19940839, 27225849; 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: 528296). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at