ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.5090G>A (p.Gly1697Asp)

dbSNP: rs752432638
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000673778 SCV000799021 uncertain significance Autosomal recessive polycystic kidney disease 2018-04-05 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000788571 SCV000927726 uncertain significance not provided 2018-06-05 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000673778 SCV000953441 uncertain significance Autosomal recessive polycystic kidney disease 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 1697 of the PKHD1 protein (p.Gly1697Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs752432638, ExAC 0.005%). This variant has not been reported in the literature in individuals with PKHD1-related disease. ClinVar contains an entry for this variant (Variation ID: 557612). 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: "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.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001292403 SCV001480782 uncertain significance Polycystic kidney disease no assertion criteria provided clinical testing The PKHD1 p.Gly1697Asp variant was not identified in the literature nor was it identified in the ClinVar, COGR, LOVD 3.0, or the RWTH AAachen University ARPKD databases. The variant was identified in dbSNP (ID: rs752432638) and in control databases in 3 of 246152 chromosomes at a frequency of 0.00001 increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017); it was identified in the following populations: Latino in 1 of 33580 chromosomes (frequency: 0.00003 and European Non-Finnish in 2 of 111626 chromosomes (frequency: 0.00002). The p.Gly1697 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc. RCV000673778 SCV002078094 uncertain significance Autosomal recessive polycystic kidney disease 2021-03-01 no assertion criteria provided clinical testing

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