rs137852944
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM5PP5_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
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive polycystic kidney diseaseInheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
- polycystic kidney disease 4Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
- Caroli diseaseInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 10 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PKHD1 | NM_138694.4 | c.107C>T | p.Thr36Met | missense_variant | Exon 3 of 67 | ENST00000371117.8 | NP_619639.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.000454 AC: 69AN: 152074Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000446 AC: 112AN: 251318 AF XY: 0.000567 show subpopulations
GnomAD4 exome AF: 0.000578 AC: 842AN: 1457630Hom.: 0 Cov.: 28 AF XY: 0.000557 AC XY: 404AN XY: 725524 show subpopulations
Age Distribution
GnomAD4 genome 0.000453 AC: 69AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28AN XY: 74394 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Polycystic kidney disease 4 Pathogenic:16
This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 (v2) for a recessive condition (144 heterozygotes, 0 homozygotes); 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); Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from threonine to methionine; This variant is heterozygous; This gene is associated with autosomal recessive disease; however, there are emerging reports of heterozygous carriers of PKHD1 variants developing liver cysts and nephrocalcinosis (PMID: 21945273, 36691356); Multiple alternative amino acid changes at the same position have been observed in gnomAD (highest allele count: 1 heterozygote, 0 homozygotes); Variant is not located in an established domain, motif, hotspot or informative constraint region; 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); Variants in this gene are known to have variable expressivity. Significant intrafamilial variability has been reported (PMID: 20301501); Inheritance information for this variant is not currently available in this individual.
ACMG codes:PS4, PM2, PM3, PP5, PP3
PM3_VeryStrong, PM2,PM5
ACMG Criteria: PS4, PM1, PM2_P, PM3, PM5_P, PP1, PP3, PP5; Variant was found in heterozygous state
ACMG classification criteria: PS4 strong, PM3 very strong, PP3 supporting
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.
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.
PM1, PM2, PP2, PP3, PP5
ACMG:PS3, PM1, PM2, PP3, PP5
not provided Pathogenic:15
PS4, PM2, PM3, PP1, PP3
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)
PKHD1: PM3:Very Strong, PP1:Strong, PM2
Autosomal recessive polycystic kidney disease Pathogenic:13
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.
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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
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).
The c.107C>T (p.Thr36Met) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This is a known Pathogenic variant that has been previously reported as a compound heterozygous and homozygous change in patients with polycystic kidney disease (PMID: 11919560, 15698423, 20413436, 15696446, 31844813, 30650191, 31980526, 33532864, 33437033, 35812281, 36307859). The c.107C>T (p.Thr36Met) variant is located in a mutational hotspot for pathogenic variations associated with polycystic kidney disease (PMID: 16199545). The c.107C>T (p.Thr36Met) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.06% (911/1609822), and is absent in the homozygous state. Based on the available evidence, c.107C>T (p.Thr36Met) is classified as Pathogenic.
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.
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.
Polycystic kidney disease Pathogenic:3
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.
PM3, PP2, PP3, PP4, PP5, BP5
Autosomal dominant polycystic liver disease Pathogenic:2
Inborn genetic diseases Pathogenic:1
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.
See cases Pathogenic:1
ACMG categories: PS3,PM2,PM3,PP3,PP5
Polycystic kidney disease;C0079924:Oligohydramnios;C1849766:Periportal fibrosis Pathogenic:1
PKHD1-related disorder Pathogenic:1
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.
Renal cyst Pathogenic:1
Colorectal cancer, protection against Benign:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at