ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.776C>T (p.Ser259Leu)

dbSNP: rs1160054242
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000591701 SCV000706663 uncertain significance not provided 2017-02-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781726 SCV000919995 uncertain significance not specified 2018-02-26 criteria provided, single submitter clinical testing Variant summary: PKHD1 c.776C>T (p.Ser259Leu) results in a non-conservative amino acid change located in the IPT domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 3/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 246194 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.776C>T in individuals affected with Polycystic Kidney and Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001829665 SCV002312824 uncertain significance Autosomal recessive polycystic kidney disease 2022-05-25 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 259 of the PKHD1 protein (p.Ser259Leu). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 500631). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Natera, Inc. RCV001829665 SCV002083391 uncertain significance Autosomal recessive polycystic kidney disease 2020-02-17 no assertion criteria provided clinical testing

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