ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.107C>T (p.Thr36Met) (rs137852944)

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Total submissions: 26
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 2017-08-08 criteria provided, single submitter clinical testing The T36M variant in the PKHD1 gene has been reported previously in multiple individuals with autosomal recessive polycystic kidney disease from a variety of ethnic backgrounds, indicating that in addition to a founder effect component, T36M may represent a mutational hotspot in the PKHD1 gene (Ward et al., 2002; Bergmann et al., 2003; Bergmann et al., 2005; Melchionda et al., 2016). The T36M variant is observed in 57/66702 (0.085%) alleles from individuals of non-Finnish European background in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). The T36M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T36M as a pathogenic variant.
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
Invitae RCV000004324 SCV000754648 pathogenic Autosomal recessive polycystic kidney disease 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 36 of the PKHD1 protein (p.Thr36Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs137852944, ExAC 0.09%). This variant has been reported extensively in individuals affected with autosomal recessive polycystic kidney disease (ARPKD) (PMID: 11919560, 16199545, 12846734, 11898128, 15108281, 12506140). It is estimated that approximately 13% of ARPKD patients of European origin have this variant, making it the most common mutation in that population (PMID: 21274727). ClinVar contains an entry for this variant (Variation ID: 4108) For these reasons, this variant has been classified as Pathogenic.
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000004324 SCV000891696 pathogenic Autosomal recessive polycystic kidney disease 2017-12-30 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000004324 SCV000894387 pathogenic Autosomal recessive polycystic kidney disease 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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, Klinikum rechts der Isar 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 Women's Health, 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 RCV000004324 SCV001427173 pathogenic Autosomal recessive polycystic kidney disease 2018-09-26 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_138694.3(PKHD1):c.107C>T, has been identified in exon 3 of 67 of the PKHD1 gene. The variant is predicted to result in a moderate amino acid change from threonine to methionine at position 36 of the protein (NP_619639.3(PKHD1):p.(Thr36Met)). The threonine at this position has very high conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.05% (142 heterozygotes, 0 homozygotes). The variant is a well known hotspot and has been previously described as pathogenic, segregating with disease in multiple families with ARPKD (OMIM, CLinVar), and at least one of the patients had p.(Arg3107*) on the other allele (Bergmann, C. et al., 2004). Subsequent analysis of parental samples indicated this variant was paternally inherited. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
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
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 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.

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