ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs376040501
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000633428 SCV000754652 pathogenic Autosomal recessive polycystic kidney disease 2023-10-04 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 375 of the PKHD1 protein (p.Arg375Trp). This variant is present in population databases (rs376040501, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 16133180, 19940839, 27225849; Invitae). 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: 528296). 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 expected to disrupt PKHD1 protein function. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000633428 SCV001163071 likely pathogenic Autosomal recessive polycystic kidney disease criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001784205 SCV002024650 likely pathogenic Polycystic kidney disease 4 2020-05-04 criteria provided, single submitter clinical testing
3billion RCV001784205 SCV002573092 likely pathogenic Polycystic kidney disease 4 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.66; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000528296). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 27225849). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx RCV000681916 SCV003915081 likely pathogenic not provided 2023-04-07 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30586318, 19940839, 31730820, 27225849, 16133180, 33123899)
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center RCV001784205 SCV004037353 likely pathogenic Polycystic kidney disease 4 2020-02-24 criteria provided, single submitter clinical testing The c.1123C>T variant is a heterozygous single base pair substitution at nucleotide 1123 in exon 15 of 67 of the PKHD1 gene, resulting in the substitution of a well-conserved, positively charged, Arginine residue at amino acid position 375 to a non-polar Tryptophan residue. The c.1123C>T variant is observed in the Genome Aggregation Database (gnomAD) in heterozygous but not homozygous form indicating it is not a common benign variant in the populations represented in this database. This variant has been observed in trans with a pathogenic variant in individuals with AR Polycystic Kidney Disease (PMID: 16133180, 30595564, 27225849). This variant is classified as likely pathogenic.
Baylor Genetics RCV001784205 SCV004202250 likely pathogenic Polycystic kidney disease 4 2023-10-10 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000681916 SCV004226559 likely pathogenic not provided 2022-05-10 criteria provided, single submitter clinical testing PP4, PM2, PM3_strong, PS4_moderate
Gharavi Laboratory, Columbia University RCV000681916 SCV000809399 likely pathogenic not provided 2018-09-16 no assertion criteria provided research
Genomics And Bioinformatics Analysis Resource, Columbia University RCV001784205 SCV004024147 likely pathogenic Polycystic kidney disease 4 no assertion criteria provided research

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