rs786204529
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_138694.4(PKHD1):c.2279G>A(p.Arg760His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000112 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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. R760W) has been classified as Likely benign.
Frequency
Consequence
NM_138694.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.2279G>A | p.Arg760His | missense_variant, splice_region_variant | 22/67 | ENST00000371117.8 | NP_619639.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.2279G>A | p.Arg760His | missense_variant, splice_region_variant | 22/67 | 1 | NM_138694.4 | ENSP00000360158.3 | ||
PKHD1 | ENST00000340994.4 | c.2279G>A | p.Arg760His | missense_variant, splice_region_variant | 22/61 | 5 | ENSP00000341097.4 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251138Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135728
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461670Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727124
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74350
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 760 of the PKHD1 protein (p.Arg760His). This variant also falls at the last nucleotide of exon 22, which is part of the consensus splice site for this exon. This variant is present in population databases (rs745770404, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 11898128, 15698423, 20413436). 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: 188876). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24984783). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | - | The heterozygous p.Arg760His variant was identified in the compound heterozygous state by our study in one individual with autosomal recessive polycystic kidney disease. The p.Arg760His variant is believed to be pathogenic based on numberous reports by other laboratories in the literature (Onuchic 2002, Bergmann 2005, Sharp 2005, Gunay-Aygun 2010). - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jul 11, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 28, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | research | Molecular Biology Laboratory, Fundació Puigvert | Feb 01, 2020 | - - |
Polycystic kidney disease 4 Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 10, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2024 | - - |
PKHD1-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 06, 2024 | The PKHD1 c.2279G>A variant is predicted to result in the amino acid substitution p.Arg760His. This substitution occurs at the last nucleotide of exon 22 and is predicted to substantially affect normal splicing by available splicing prediction programs (Alamut Visual Plus v1.6.1). This variant has been reported in individuals with autosomal recessive polycystic kidney disease (ARPKD) (Onuchic et al. 2002. PubMed ID: 11898128; Jordan et al. 2022. PubMed ID: 35005812). Of note, we have previously observed this variant at PreventionGenetics in the homozygous state in an affected child and the heterozygous state in other PKD patients who have another pathogenic PKHD1 variant. The c.2279G>A variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at