ClinVar Miner

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

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Total submissions: 18
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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 dysplasia; 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.
Integrated Genetics/Laboratory Corporation of America 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 dysplasia 2017-01-01 criteria provided, single submitter clinical testing
Invitae RCV000004324 SCV000754648 pathogenic Autosomal recessive polycystic kidney disease 2019-12-20 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
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

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