ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.8068T>C (p.Trp2690Arg) (rs886061616)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000299549 SCV000464057 likely pathogenic Autosomal recessive polycystic kidney disease 2018-02-20 criteria provided, single submitter clinical testing The PKHD1 c.8068T>C (p.Trp2690Arg) missense variant has been reported in a compound heterozygous state in four individuals, including a sibling pair, diagnosed with autosomal recessive polycystic kidney disease (Sgro et al. 2004; Bergmann et al. 2005; Michel-Calemard et al. 2009; Gunay-Aygun et al. 2010). The variant was absent from at least 604 control chromosomes and is reported at a frequency of 0.000027 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Trp2690Arg variant is classified as likely pathogenic for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000522783 SCV000617330 likely pathogenic not provided 2017-08-08 criteria provided, single submitter clinical testing The W2690R variant in the PKHD1 gene has been reported previously in the heterozygous state with another disease-causing variant in patients with ARPKD and Caroli disease (Sgro et al, 2004; Michel-Calemard et al., 2009; Gunay-Aygun et al., 2010; Gunay-Aygun et al., 2011). The W2690R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The W2690R 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret W2690R as a likely pathogenic variant.
Invitae RCV000299549 SCV000955186 likely pathogenic Autosomal recessive polycystic kidney disease 2019-08-26 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 2690 of the PKHD1 protein (p.Trp2690Arg). The tryptophan residue is moderately conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with autosomal recessive polycystic kidney disease (PMID: 14971004, 15698423, 20413436, 19021639). 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: 357427). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics RCV000299549 SCV001163029 likely pathogenic Autosomal recessive polycystic kidney disease criteria provided, single submitter clinical testing
Counsyl RCV000299549 SCV000793739 likely pathogenic Autosomal recessive polycystic kidney disease 2017-08-29 no assertion criteria provided clinical testing

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