ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.934C>T (p.Arg312Trp)

gnomAD frequency: 0.00010  dbSNP: rs372340268
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000594091 SCV000709035 uncertain significance not provided 2018-01-29 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002476337 SCV000897304 uncertain significance Polycystic kidney disease 4 2022-03-08 criteria provided, single submitter clinical testing
Invitae RCV000765893 SCV001230957 uncertain significance Autosomal recessive polycystic kidney disease 2021-11-28 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 312 of the PKHD1 protein (p.Arg312Trp). This variant is present in population databases (rs372340268, gnomAD 0.06%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 33123899). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 502343). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PKHD1 protein function. 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. RCV000765893 SCV001463520 uncertain significance Autosomal recessive polycystic kidney disease 2017-11-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001292464 SCV001481026 uncertain significance Polycystic kidney disease no assertion criteria provided clinical testing The PKHD1 p.Arg312Trp variant was not identified in the literature nor was it identified in the ClinVar, LOVD 3.0, or the RWTH AAachen University ARPKD database. The identification of this variant in one individual by our laboratory with ARPKD and a co-occurring pathogenic variant in ARPKD, increases the likelihood, this variant may have clinical significance. The variant was identified in dbSNP (ID: rs372340268) as “NA”, and in control databases in 33 of 275364 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 2 of 23724 chromosomes (freq: 0.00008), European Non-Finnish in 11 of 125766 chromosomes (freq: 0.00009), and South Asian in 20 of 30782 chromosomes (freq: 0.0007) and was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, and European Finnish populations. The p.Arg312 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.

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