ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.4870C>T (p.Arg1624Trp) (rs200391019)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168407 SCV000219101 pathogenic Autosomal recessive polycystic kidney disease 2020-10-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1624 of the PKHD1 protein (p.Arg1624Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs200391019, ExAC 0.03%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in numerous individuals affected with autosomal recessive polycystic kidney disease (PMID: 16133180, 26695994, 19914852, 27225849, Invitae). This finding is consistent with autosomal recessive inheritance and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 188369). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000479548 SCV000229571 pathogenic not provided 2017-04-17 criteria provided, single submitter clinical testing
GeneDx RCV000479548 SCV000568261 pathogenic not provided 2017-02-02 criteria provided, single submitter clinical testing The R1624W variant in the PKDH1 gene has been reported previously in the homozygous and compound heterozygous state in individuals with perinatal and non-perinatal presentation of autosomal recessive polycystic kidney disease (Onuchic et al., 2002; Gunay-Aygun et al., 2010; Losekoot et al., 2015; Edrees et al., 2016). The R1624W variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1624W 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. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R1624W as a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000168407 SCV000611296 pathogenic Autosomal recessive polycystic kidney disease 2017-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000168407 SCV000699865 pathogenic Autosomal recessive polycystic kidney disease 2016-07-08 criteria provided, single submitter clinical testing Variant summary: The PKHD1 c.4870C>T (p.Arg1624Trp) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not functional for this variant). This variant was found in 22/121594 control chromosomes at a frequency of 0.0001809, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). This variant has been reported in at least 6 ARPKD patients in heterozygous or homozygous state (Obeidova_2015, Sharp_2005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626996 SCV000747699 pathogenic Abnormality of the intrahepatic bile duct 2017-01-01 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000168407 SCV000803436 uncertain significance Autosomal recessive polycystic kidney disease 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Polycystic kidney disease autosomal recessive. The following ACMG Tag(s) were applied: PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:16133180). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Supporting => Recurrent mutation (PMID:11898128) (PMID:12874454) (PMID:19914852).
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000168407 SCV000891697 pathogenic Autosomal recessive polycystic kidney disease 2017-12-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000168407 SCV000916155 pathogenic Autosomal recessive polycystic kidney disease 2017-09-08 criteria provided, single submitter clinical testing Across a selection of the available literature, the PKHD1 c.4870C>T (p.Arg1624Trp) missense variant has been identified in a total of nine individuals with autosomal recessive polycystic kidney disease (ARPKD), including two siblings from a consanguineous union who presented a milder, later-onset phenotype and carried the variant in a homozygous state, six individuals who carried the variant in a compound heterozygous state and presented a range of phenotypes, and one individual with a milder, later-onset phenotype who was heterozygous for the variant (Onuchic et al. 2002; Losekoot et al. 2005; Gunay-Aygun et al. 2010). The p.Arg1624Trp variant was also identified in a heterozygous state in a total of four unaffected parents of individuals with ARPKD and was absent from 60 controls (Onuchic et al. 2002). The variant is reported at a frequency of 0.000464 in the Other population of the Genome Aggregation Database. Based on the collective evidence, the p.Arg1624Trp 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.
Baylor Genetics RCV000168407 SCV001163046 pathogenic Autosomal recessive polycystic kidney disease criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000168407 SCV001194097 pathogenic Autosomal recessive polycystic kidney disease 2019-12-26 criteria provided, single submitter clinical testing NM_138694.3(PKHD1):c.4870C>T(R1624W) is classified as pathogenic in the context of PKHD1-related autosomal recessive polycystic kidney disease. Sources cited for classification include the following: PMID 27225849, 16133180, 19914852 and 11898128. Classification of NM_138694.3(PKHD1):c.4870C>T(R1624W) 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000479548 SCV001246966 pathogenic not provided 2017-10-01 criteria provided, single submitter clinical testing
Laboratory of Molecular Genetics,Children's Memorial Health Institute RCV000168407 SCV001434248 likely pathogenic Autosomal recessive polycystic kidney disease 2020-09-25 criteria provided, single submitter clinical testing
Baylor Genetics RCV001331702 SCV001523800 pathogenic Polycystic kidney disease 4 2020-08-13 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Laboratory of Molecular Diagnosis of Genetic Disease,Università degli Studi di Napoli Federico II RCV001507098 SCV001712069 likely pathogenic Caroli disease 2021-05-05 criteria provided, single submitter clinical testing
Gharavi Laboratory,Columbia University RCV000479548 SCV000809270 likely pathogenic not provided 2018-09-16 no assertion criteria provided research
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000168407 SCV001133172 likely pathogenic Autosomal recessive polycystic kidney disease 2019-09-26 no assertion criteria provided clinical testing
Institute of Human Genetics, Klinikum rechts der Isar RCV000168407 SCV001149876 pathogenic Autosomal recessive polycystic kidney disease 2019-06-07 no assertion criteria provided clinical testing
Sydney Genome Diagnostics,Children's Hospital Westmead RCV000168407 SCV001449401 pathogenic Autosomal recessive polycystic kidney disease 2018-07-24 no assertion criteria provided clinical testing This individual is heterozygous for the c.4870C>T variant in the PKHD1 gene. This variant has been reported in the literature in several different families with autosomal recessive polycystic kidney disease (ARPKD) as both homozygous and compound heterozygous, usually associated with a late onset or milder phenotype (e.g. Onuchic et al 2002 Am J Hum Genet 70: 1305-1317; Sharp et al 2005 J Met Genet 42: 336-349; ). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a low allele frequency of 0.014% (40 out of 277,158 alleles). This variant is considered to be pathogenic according to the ACMG guidelines.
Natera, Inc. RCV000168407 SCV001459198 pathogenic Autosomal recessive polycystic kidney disease 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001292108 SCV001480940 likely pathogenic Polycystic kidney disease no assertion criteria provided clinical testing The PKHD1 p.Arg1624Trp variant was identified in 28 of 696 proband chromosomes (frequency: 0.04) from individuals or families with ARPKD and was not identified in 200 control chromosomes from healthy individuals (Edrees 2016,Gunay-Aygun 2010, Losekoot 2005, Melchionda 2016, Obeidova 2015, Sharp 2005). The variant was also identified in dbSNP (ID: rs200391019) as "With Pathogenic allele ", ClinVar (classified as pathogenic by Invitae, GeneDx and four clinical laboratories; as likely pathogenic by Counsyl; as uncertain significance by SIB Swiss Institute of Bioinformatics), LOVD 3.0 (3x), and in RWTH AAachen University ARPKD database (as pathogenic or probably pathogenic), databases. The variant was not identified in COGR database. The variant was identified in control databases in 40 of 277158 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24036 chromosomes (freq: 0.00004), Other in 3 of 6464 chromosomes (freq: 0.0005), Latino in 4 of 34420 chromosomes (freq: 0.0001), European in 28 of 126656 chromosomes (freq: 0.0002), Ashkenazi Jewish in 1 of 10144 chromosomes (freq: 0.0001), and South Asian in 3 of 30780 chromosomes (freq: 0.0001), while the variant was not observed in the East Asian, or Finnish populations. The p.Arg1624 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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