ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.1123C>T (p.Arg375Trp) (rs376040501)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Gharavi Laboratory,Columbia University RCV000681916 SCV000809399 likely pathogenic not provided 2018-09-16 no assertion criteria provided research
Invitae RCV000633428 SCV000754652 uncertain significance Autosomal recessive polycystic kidney disease 2017-08-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 375 of the PKHD1 protein (p.Arg375Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs376040501, ExAC 0.02%). This variant has been observed on the opposite chromosome (in trans) from other pathogenic variants in individuals affected with autosomal recessive polycystic kidney disease (ARPKD) (PMID: 16133180, 27225849). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease.  Additionally, a fetus affected with ARPKD was reported to carry this variant along with a second, rare missense change in PKHD1 (PMID: 19940839). 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, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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