ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
Counsyl RCV000168407 SCV000486181 likely pathogenic Autosomal recessive polycystic kidney disease 2016-04-12 criteria provided, single submitter clinical testing
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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000479548 SCV000229571 pathogenic not provided 2017-04-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000168407 SCV000611296 pathogenic Autosomal recessive polycystic kidney disease 2017-05-18 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.
Gharavi Laboratory,Columbia University RCV000479548 SCV000809270 likely pathogenic not provided 2018-09-16 no assertion criteria provided research
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.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000168407 SCV000219101 pathogenic Autosomal recessive polycystic kidney disease 2018-12-06 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 database). 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"). In summary, this is a rare missense change that has been observed in trans with a pathogenic variant in numerous affected individuals. For these reasons, this variant has been classified as Pathogenic.
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).

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