rs146649803
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong
The NM_138694.4(PKHD1):c.9719G>T(p.Arg3240Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000173 in 1,613,858 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3240Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.9719G>T | p.Arg3240Leu | missense_variant | 58/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.9719G>T | p.Arg3240Leu | missense_variant | 58/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.9719G>T | p.Arg3240Leu | missense_variant | 58/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152114Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251240Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135768
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461744Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14AN XY: 727182
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152114Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74298
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); 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: 9511976, 15805161) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 11, 2014 | - - |
PKHD1-related condition Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 11, 2022 | The PKHD1 c.9719G>T variant is predicted to result in the amino acid substitution p.Arg3240Leu. This variant was reported along with a second PKHD1 variant in a prenatal case of autosomal recessive polycystic kidney disease (ARPKD) (Sharp et al. 2005. PubMed ID: 15805161). Internally, we have observed this variant in the compound heterozygous state with a second PKHD1 variant in two families with individuals affected with ARPKD. An alternate substitution impacting the same amino acid (p.Arg3240Gln) has also been reported in patients with ARPKD (e.g., Bergmann et al. 2005. PubMed ID: 15698423; https://www.ncbi.nlm.nih.gov/clinvar/variation/572902). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51612695-C-A). Taken together, this variant is interpreted as likely pathogenic. - |
Autosomal recessive polycystic kidney disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 08, 2023 | ClinVar contains an entry for this variant (Variation ID: 167478). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 3240 of the PKHD1 protein (p.Arg3240Leu). This variant is present in population databases (rs146649803, gnomAD 0.0009%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 15805161). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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. This variant disrupts the p.Arg3240 amino acid residue in PKHD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15698423, 19914852, 20413436, 24162162). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Polycystic kidney disease 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 04, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 11, 2017 | Variant summary: The c.9719G>T (pArg3240Leu) in PKHD1 gene is a missense variant involves a conserved nucleotide located outside of any known functional domain or repeat. The 4/4 in silico tools used predict damaging outcome for this variant, however no functional studies supporting these predictions were published at the time of evaluation. The c.9719G>T was identified in the control population dataset of gnomAD at a low frequency of 0.000004 (1/245990 chrs tested). The observed frequencies do not exceed the maximum expected allele frequency for a pathogenic variant of 0.007, suggesting that it is not a common polymorphism. The variant has been reported in compound heterozygosity in 1 fetal sample with confirmed dx of ARPKD and is cited as VUS/Likely Pathogenic by reputable databases/clinical laboratories. In addition, other alterations of Arg3240 codon have been reported in association with ARPKD. Taken together, the variant was classified as VUS-Possibly Pathogenic, until new information becomes available. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at