ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.7264T>G (p.Cys2422Gly) (rs201881567)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000457585 SCV000799602 uncertain significance Autosomal recessive polycystic kidney disease 2018-04-27 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000729736 SCV000857423 uncertain significance not provided 2017-10-12 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000457585 SCV000915170 uncertain significance Autosomal recessive polycystic kidney disease 2018-08-21 criteria provided, single submitter clinical testing The PKHD1 c.7264T>G (p.Cys2422Gly) missense variant has been reported in two studies and found in a total of four individuals with autosomal recessive polycystic kidney disease, including three individuals from two families in a compound heterozygous state and one neonate in a heterozygous state in whom a second variant was not identified (Furu et al. 2003; Bergmann et al. 2005). In all the three compound heterozygous individuals, the p.Cys2422Gly variant was found in trans with an established pathogenic variant, p.Thr36Met. The p.Cys2422Gly variant was absent from a total of 360 controls and is reported at a frequency of 0.00378 in the European (Finnish) population of the Exome Aggregation Consortium. One homozygote is reported in the European (Finnish) population of the Genome Aggregation Database. The evidence for this variant is limited. The p.Cys2422Gly variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000457585 SCV000545843 uncertain significance Autosomal recessive polycystic kidney disease 2016-11-07 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 2422 of the PKHD1 protein (p.Cys2422Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is present in population databases (rs201881567, ExAC 0.4%). This variant has been reported in individuals and families affected with autosomal recessive polycystic kidney disease (PMID: 12874454, 15698423). In several of these individuals, the variant was in trans (on the opposite allele) with a pathogenic variant. However, currently there is insufficient evidence to conclude whether this variant segregates with disease or not. 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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