ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.2279G>A (p.Arg760His) (rs745770404)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169230 SCV000220499 likely pathogenic Autosomal recessive polycystic kidney disease 2014-07-11 criteria provided, single submitter literature only
Broad Institute Rare Disease Group,Broad Institute RCV000169230 SCV000786708 pathogenic Autosomal recessive polycystic kidney disease criteria provided, single submitter research The heterozygous p.Arg760His variant was identified in the compound heterozygous state by our study in one individual with autosomal recessive polycystic kidney disease. The p.Arg760His variant is believed to be pathogenic based on numberous reports by other laboratories in the literature (Onuchic 2002, Bergmann 2005, Sharp 2005, Gunay-Aygun 2010).
Invitae RCV000169230 SCV001415899 pathogenic Autosomal recessive polycystic kidney disease 2019-10-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 760 of the PKHD1 protein (p.Arg760His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant also falls at the last nucleotide of exon 22 of the PKHD1 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs745770404, ExAC 0.01%). This variant has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 11898128, 15698423, 20413436). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188876). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 24984783). For these reasons, this variant has been classified as Pathogenic.

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