Submissions for variant NM_138694.4(PKHD1):c.107C>T (p.Thr36Met)

gnomAD frequency: 0.00048  dbSNP: rs137852944

Total submissions: 48

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082517	SCV000229254	pathogenic	not provided	2017-02-20	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000082517	SCV000280607	pathogenic	not provided	2015-12-21	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414898	SCV000493030	pathogenic	Polycystic kidney disease; Oligohydramnios; Periportal fibrosis	2014-03-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000082517	SCV000616822	pathogenic	not provided	2020-01-10	criteria provided, single submitter	clinical testing	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)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004324	SCV000699843	pathogenic	Autosomal recessive polycystic kidney disease	2017-04-13	criteria provided, single submitter	clinical testing	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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626993	SCV000747696	pathogenic	Polycystic kidney disease	2017-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000004324	SCV000754648	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing	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.
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000004324	SCV000891696	pathogenic	Autosomal recessive polycystic kidney disease	2017-12-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001535891	SCV000894387	pathogenic	Polycystic kidney disease 4	2022-04-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000004324	SCV000915174	pathogenic	Autosomal recessive polycystic kidney disease	2018-09-19	criteria provided, single submitter	clinical testing	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.
Blueprint Genetics	RCV000082517	SCV000928163	pathogenic	not provided	2019-01-11	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000004324	SCV001149878	pathogenic	Autosomal recessive polycystic kidney disease	2018-04-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000004324	SCV001163086	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000004324	SCV001194068	pathogenic	Autosomal recessive polycystic kidney disease	2019-10-18	criteria provided, single submitter	clinical testing	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.
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV000082517	SCV001422383	pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Molecular Biology Laboratory, Fundació Puigvert	RCV000004324	SCV001425221	likely pathogenic	Autosomal recessive polycystic kidney disease	2020-02-01	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001535891	SCV001427173	pathogenic	Polycystic kidney disease 4	2023-07-17	criteria provided, single submitter	clinical testing	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) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (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
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV000626993	SCV001431015	likely pathogenic	Polycystic kidney disease	2020-05-28	criteria provided, single submitter	research	PM3, PP2, PP3, PP4, PP5, BP5
Laboratory of Molecular Genetics, Children's Memorial Health Institute	RCV000004324	SCV001434254	pathogenic	Autosomal recessive polycystic kidney disease	2020-09-25	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000082517	SCV001468094	pathogenic	not provided	2020-09-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000082517	SCV001713353	pathogenic	not provided	2020-12-31	criteria provided, single submitter	clinical testing	PS4, PM2, PM3, PP1, PP3
Fulgent Genetics, Fulgent Genetics	RCV001535891	SCV001752523	pathogenic	Polycystic kidney disease 4	2021-06-30	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001535891	SCV001870375	pathogenic	Polycystic kidney disease 4	2021-07-29	criteria provided, single submitter	research	ACMG codes:PS4, PM2, PM3, PP5, PP3
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001535891	SCV001984626	pathogenic	Polycystic kidney disease 4	2020-08-18	criteria provided, single submitter	clinical testing
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS	RCV001535891	SCV002099438	pathogenic	Polycystic kidney disease 4		criteria provided, single submitter	research
Molecular Genetics, Royal Melbourne Hospital	RCV001535891	SCV002503829	pathogenic	Polycystic kidney disease 4	2020-12-17	criteria provided, single submitter	clinical testing	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.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001535891	SCV002577587	pathogenic	Polycystic kidney disease 4	2021-10-12	criteria provided, single submitter	clinical testing	PM1, PM2, PP2, PP3, PP5
Institute of Human Genetics, University Hospital Muenster	RCV004584312	SCV002577854	pathogenic	See cases	2021-12-21	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PM2,PM3,PP3,PP5
MGZ Medical Genetics Center	RCV001535891	SCV002581890	pathogenic	Polycystic kidney disease 4	2022-09-05	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001535891	SCV003807146	pathogenic	Polycystic kidney disease 4	2022-04-25	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 strong, PM3 very strong, PP3 supporting
Neuberg Centre For Genomic Medicine, NCGM	RCV001535891	SCV004048579	pathogenic	Polycystic kidney disease 4		criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV001535891	SCV004202217	pathogenic	Polycystic kidney disease 4	2024-03-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018552	SCV005006765	pathogenic	Inborn genetic diseases	2022-06-02	criteria provided, single submitter	clinical testing	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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000082517	SCV005197172	pathogenic	not provided	2023-03-02	criteria provided, single submitter	clinical testing
OMIM	RCV000004324	SCV000024495	pathogenic	Autosomal recessive polycystic kidney disease	2011-03-01	no assertion criteria provided	literature only
OMIM	RCV000023566	SCV000044857	protective	Colorectal cancer, protection against	2011-03-01	no assertion criteria provided	literature only
Yale Center for Mendelian Genomics, Yale University	RCV000845138	SCV000987074	likely pathogenic	Autosomal dominant polycystic liver disease	2017-04-04	no assertion criteria provided	literature only
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV000004324	SCV001449403	pathogenic	Autosomal recessive polycystic kidney disease	2018-11-23	no assertion criteria provided	clinical testing	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000626993	SCV001480955	pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	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.
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV000845138	SCV001876996	likely pathogenic	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000082517	SCV001977670	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000082517	SCV001978377	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000082517	SCV001978581	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000082517	SCV001979725	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000082517	SCV002036971	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000004324	SCV002083426	pathogenic	Autosomal recessive polycystic kidney disease	2017-03-17	no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV001535891	SCV002106589	pathogenic	Polycystic kidney disease 4	2019-02-14	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003415647	SCV004116608	pathogenic	PKHD1-related disorder	2024-09-04	no assertion criteria provided	clinical testing	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 (see for example, Ward et al. 2002. PubMed ID: 11919560; Bergmann et al. 2003. PubMed ID: 12506140; Obeidova et al. 2020. PubMed ID: 32574212). This variant is reported in 0.093% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.