rs137852944
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong
The NM_138694.4(PKHD1):c.107C>T(p.Thr36Met) variant causes a missense change. The variant allele was found at a frequency of 0.000566 in 1,609,822 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T36A) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00058 ( 0 hom. )
Consequence
PKHD1
NM_138694.4 missense
NM_138694.4 missense
Scores
6
11
2
Clinical Significance
Conservation
PhyloP100: 5.70
Genes affected
PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr6-52083202-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1515136.Status of the report is criteria_provided_single_submitter, 1 stars.
PP5
?
Variant 6-52083201-G-A is Pathogenic according to our data. Variant chr6-52083201-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52083201-G-A is described in Lovd as [Pathogenic]. Variant chr6-52083201-G-A is described in Lovd as [Likely_pathogenic]. Variant chr6-52083201-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| PKHD1 | NM_138694.4 | c.107C>T | p.Thr36Met | missense_variant | 3/67 | ENST00000371117.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PKHD1 | ENST00000371117.8 | c.107C>T | p.Thr36Met | missense_variant | 3/67 | 1 | NM_138694.4 | P2 | |
| PKHD1 | ENST00000340994.4 | c.107C>T | p.Thr36Met | missense_variant | 3/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000454 AC: 69AN: 152074Hom.: 0 Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:46Benign:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Polycystic kidney disease 4 Pathogenic:13
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 12, 2021 | PM1, PM2, PP2, PP3, PP5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
| Pathogenic, criteria provided, single submitter | research | Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS | - | - - |
| Pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Feb 14, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital | Aug 18, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Mar 31, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 4, with or without hepatic disease (MIM#263200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2) for a recessive condition (144 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (highest allele count: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated IPT/TIG 1 motif (PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with autosomal recessive polycystic kidney disease (ARPKD) (ClinVar; PMID: 27225849, PMID: 32799815). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Dec 17, 2020 | This sequence change is predicted to replace threonine with methionine at codon 36 of the PKHD1 protein (p.(Thr36Met)). The threonine residue is highly conserved (100 vertebrates, UCSC), and is located in the IPT 1 domain. There is a moderate physicochemical difference between threonine and methionine. The variant is present in a large population cohort at a frequency of 0.05% (rs137852944, 144/282,706 alleles, 0 homozygotes in gnomAD v2.1). This is a recurrent mutation that has been identified in the homozygous and compound heterozygous with a second pathogenic allele in multiple individuals with autosomal recessive polycystic kidney disease ranging from severe to moderate phenotypes, and segregates with disease in multiple families (PMID: 11898128, 12506140). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PP3. - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Jul 29, 2021 | ACMG codes:PS4, PM2, PM3, PP5, PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 05, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 26, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Apr 25, 2022 | ACMG classification criteria: PS4 strong, PM3 very strong, PP3 supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense c.107C>T (p.Thr36Met) variant in PKHD1 gene has been reported in heterozygous and homozygous state in individuals affected with autosomal recessive polycystic kidney disease (Ward, Christopher J et al.,2002; Furu, Laszlo et al.,2004). The variant is a well known hotspot and has been previously described as pathogenic, segregating with disease in multiple families with ARPKD (Bergmann, C. et al., 2004). The variant is reported with the allele frequency 0.05% in the gnomAD and 0.01% in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic / Likely Pathogenic. The amino acid Thr at position 36 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Thr36Met in PKHD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
Autosomal recessive polycystic kidney disease Pathogenic:12
| Pathogenic, no assertion criteria provided | clinical testing | Sydney Genome Diagnostics, Children's Hospital Westmead | Nov 23, 2018 | This individual is heterozygous for the c.107C>T variant in the PKHD1 gene, which results in the amino acid substitution of threonine to methionine at residue 36, p.(Thr36Met). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with an allele frequency of 0.05% (144 out of 282,706 alleles). This variant, either observed as homozygous or compound heterozygous with another pathogenic variant, has been previously reported in patients with autosomal recessive polycystic kidney disease (ARPKD; Bergmann et al 2005 Kid Int 67: 829-848, Bergmann et al 2003 J Am Soc Nephrol 13: 76-89, Obeidova et al 2015 BMC Med Genet 16:116). This variant accounts for approximately 15% of alleles in ARPKD patient of European ancestry. This variant is considered to pathogenic according to the ACMG guidelines (Evidence used: PM3_very strong, PP3, PP5). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics, Children's Memorial Health Institute | Sep 25, 2020 | - - |
| Likely pathogenic, criteria provided, single submitter | research | Molecular Biology Laboratory, Fundació Puigvert | Feb 01, 2020 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2011 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 19, 2018 | Across a selection of the available literature, the PKHD1 c.107C>T (p.Thr36Met) missense variant has been observed in a total of 81 individuals with autosomal recessive polycystic kidney disease, including in eight in a homozygous state (of whom two were siblings), in 42 in a compound heterozygous state, and in 37 in a heterozygous state (Ward et al. 2002; Bergmann et al. 2003; Furu et al. 2003; Sharp et al. 2005; Gunay-Aygun et al. 2010; Liu et al. 2014; Obeidova et al. 2015). Haplotype analysis studies indicate that the p.Thr36Met variant occurs in a mutational hotspot (Bergmann et al. 2004), and suggest that the variant may have a single European origin (Consugar et al. 2005). This variant was absent from 510 controls but is reported at a frequency of 0.000932 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Thr36Met variant is classified as pathogenic for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Apr 23, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 36 of the PKHD1 protein (p.Thr36Met). This variant is present in population databases (rs137852944, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (ARPKD) (PMID: 11898128, 11919560, 12506140, 12846734, 15108281, 16199545, 21274727). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of European ancestry (PMID: 21274727). ClinVar contains an entry for this variant (Variation ID: 4108). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 18, 2019 | NM_138694.3(PKHD1):c.107C>T(T36M) is classified as pathogenic in the context of autosomal recessive polycystic kidney disease, PKHD1-related. Sources cited for classification include the following: PMID 12506140, 16133180, 12846734 and 19914852. Classification of NM_138694.3(PKHD1):c.107C>T(T36M) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 13, 2017 | Variant summary: The PKHD1 c.107C>T (p.Thr36Met) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant. This variant was found in 78/128548 control chromosomes at a frequency of 0.0006068, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). This variant has been reported in many ARPKD patients both as compound heterozygotes and homozygotes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. One study of European cohorts detected more variant carriers in controls than in CRC patients, indicating a possibly protective role of variant against CRC (Ward_2011). Taken together, this variant is classified as pathogenic for ARPKD. - |
not provided Pathogenic:12
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research | Jan 01, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Sep 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 20, 2017 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Dec 21, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 10, 2020 | T63M has been described as a founder mutation that constitutes every fifth PKHD1 variant and may represent a mutational hotspot in the PKHD1 gene (Bergmann et al., 2005); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19914852, 15108277, 11898128, 26695994, 20490649, 27225849, 21274727, 11919560, 20413436, 12846734, 15805161, 16523049, 16133180, 20575693, 18503009, 23582048, 12506140, 27752906, 26721323, 28753889, 15706593, 15698423, 28375157, 30773290, 30650191, 31844813, 32799815, 31980526, 32574212, 31589614, 33258288, 32359821) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 31, 2020 | PS4, PM2, PM3, PP1, PP3 - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jan 11, 2019 | - - |
Polycystic kidney disease Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKHD1 p.Thr36Met variant was identified in 119 of 1331 proband chromosomes (frequency: 0.0939) from individuals or families with autosomal recessive hereditary polycystic kidney disease (ARPKD) (Adeva 2006, Bergmann 2003, Bergmann 2004a, Bergmann 2004b, Bergmann 2005, Denamur 2010, Furu 2004 , Gunay-Aygun 2010, Losekoot 2005, Rosetti 2003, Sharp 2005). The variant was also identified in dbSNP (ID: rs137852944) as “with pathogenic allele”, in ClinVar (as pathogenic by Emory Genetics, Center for Pediatric Genomic Medicine, Centre for Medelian Genomics and OMIM), LOVD 3.0, RWTH AAachen University ARPKD database (probably pathogenic). The variant was identified in control databases in 142 of 277030 chromosomes at a frequency of 0.000513 (Genome Aggregation Consortium Feb 27, 2017). The p.Thr36Met variant has been described in various PKHD1 mutation studies to date and accounts for approximately 20% of pathogenic alleles in PKHD1 (Bergmann, 2005). The variant may represent a founder effect in the Central European population where it is particularly frequent (Bergmann, 2005). However, there is compelling evidence that p.Thr36Met constitutes a mutational “hotspot,” most likely due to methylation induced deamination of the mutagenic CpG dinucleotide (Bergmann 2005). Study subjects with the p.Thr36Met variant are ethnically diverse and represent the full spectrum of clinical presentations for ARPKD (Sharp 2005). Additionally, Ward et al (2011) estimated that the carrier rate for PKHD1 pathogenic variants in the European population is 3.2% and p.Thr36Met was responsible for 13.1% of mutations (Ward 2011). The p.Thr36Met amino acid substitution represents a potential alternative initiation codon that is actually predicted to be stronger than the native start codon (Furu 2004). If the alternative start site were used exclusively in vivo, then the translation product would lack the leader sequence required for proper folding and p.Thr36Met may indeed behave like a complete loss of function allele akin to the chain-terminating mutations (Furu 2004). The p.Thr36Met residue is conserved across mammals and other organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | research | Cavalleri Lab, Royal College of Surgeons in Ireland | May 28, 2020 | PM3, PP2, PP3, PP4, PP5, BP5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Autosomal dominant polycystic liver disease Pathogenic:2
| Likely pathogenic, no assertion criteria provided | research | Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center | Sep 01, 2021 | - - |
| Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Apr 04, 2017 | - - |
Kidney disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Dec 21, 2021 | ACMG categories: PS3,PM2,PM3,PP3,PP5 - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 02, 2022 | The c.107C>T (p.T36M) alteration is located in exon 3 (coding exon 2) of the PKHD1 gene. This alteration results from a C to T substitution at nucleotide position 107, causing the threonine (T) at amino acid position 36 to be replaced by a methionine (M). This common European mutation has been detected in multiple individuals with PKHD1-related polycystic kidney disease, in the homozygous state, the compound heterozygous state, and in the heterozygous state without a second alteration identified (Bergmann, 2003; Furu, 2003; Gunay-Aygun, 2010; Obeidova, 2015; Obeidova, 2020; Onuchic, 2002; Ward, 2011). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
PKHD1-related condition Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 15, 2023 | The PKHD1 c.107C>T variant is predicted to result in the amino acid substitution p.Thr36Met. This variant has been repeatedly reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) in unrelated patients of different ethnic origin (Ward et al. 2002. PubMed ID: 11919560; Bergmann et al. 2003. PubMed ID: 12506140). This variant is reported in 0.093% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Polycystic kidney disease;C0079924:Oligohydramnios;C1849766:Periportal fibrosis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 13, 2014 | - - |
Colorectal cancer, protection against Benign:1
| protective, no assertion criteria provided | literature only | OMIM | Mar 01, 2011 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
M;M
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at