Submissions for variant NM_138694.4(PKHD1):c.274C>T (p.Arg92Trp)

dbSNP: rs370277502

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000337196	SCV000340220	uncertain significance	not provided	2016-03-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004221	SCV001163085	likely pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001004221	SCV001427137	pathogenic	Autosomal recessive polycystic kidney disease	2018-11-23	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_138694.3(PKHD1):c.274C>T, has been identified in exon 4 of 67 of the PKHD1 gene. The variant is predicted to result in a major amino acid change from arginine to tryptophan at position 92 of the protein (NP_619639.3(PKHD1):p.(Arg92Trp)). The arginine residue at this position has low conservation (100 vertebrates, UCSC), and is located within the IPT functional domain. In silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.001% (3 heterozygotes, 0 homozygotes). An alternative residue change, p.(Arg92Gln) has been reported in the gnomAD database at a frequency of 0.07% (182 heterozygotes, 1 homozygote). The p.(Arg92Trp) variant has been previously described as pathogenic and segregated with disease in multiple families with Polycystic kidney disease (ClinVar, Gunay-Aygun, M. et al. (2010), Xu, Y. et al. (2014), Byun, YJ. et al. (2015), Schueler, M. et al (2016), PKHD1 Database). A different variant affecting the same amino acid resulting in a change to glycine has also been shown to cause Polycystic kidney disease (Bergmann, C. et al. (2005)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Laboratory of Molecular Genetics, Children's Memorial Health Institute	RCV001004221	SCV001434250	likely pathogenic	Autosomal recessive polycystic kidney disease	2020-09-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001535928	SCV001752582	likely pathogenic	Polycystic kidney disease 4	2021-06-30	criteria provided, single submitter	clinical testing
3billion	RCV001535928	SCV002521624	likely pathogenic	Polycystic kidney disease 4	2022-05-22	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: 0.001%). Protein truncation variants are a common disease-causing mechanism. In silico tools do not predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.01). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000286684). A different missense change at the same codon (p.Arg92Gly) has been reported to be associated with PKHD1 related disorder (PMID: 15698423). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV000337196	SCV002571385	likely pathogenic	not provided	2022-03-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: Byun_2015_article, 30275481, 32939031, 19914852, 32384486, 25153916, 33282801)
Invitae	RCV001004221	SCV003439466	pathogenic	Autosomal recessive polycystic kidney disease	2023-12-20	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 92 of the PKHD1 protein (p.Arg92Trp). This variant is present in population databases (rs370277502, gnomAD 0.007%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 19914852, 25153916, 32384486, 32939031, 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: 286684). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PKHD1 protein function. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003417901	SCV004108620	pathogenic	PKHD1-related condition	2023-08-03	criteria provided, single submitter	clinical testing	The PKHD1 c.274C>T variant is predicted to result in the amino acid substitution p.Arg92Trp. This variant alongside a pathogenic truncating PKHD1 variant has been reported in multiple individuals with autosomal recessive polycystic kidney disease (ARPKD) (Gunay-Aygun et al. 2010. PubMed ID: 19914852; Table S3, Jayasinghe et al. 2020. PubMed ID: 32939031; Jung et al. 2020. PubMed ID: 32384486). This variant has also been reported with another suspected pathogenic PKHD1 variant in a Chinese family with autosomal recessive polycystic kidney disease (ARPKD) (Xu et al. 2014. PubMed ID: 25153916). Of note, a different substitution at the same codon (p.Arg92Gly) has been reported in a patient with ARPKD (Bergmann et al. 2005. PubMed ID: 15698423). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51947197-G-A). This variant is interpreted as pathogenic.
Baylor Genetics	RCV001535928	SCV004204667	likely pathogenic	Polycystic kidney disease 4	2023-05-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001004221	SCV004241510	pathogenic	Autosomal recessive polycystic kidney disease	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.274C>T (p.Arg92Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251230 control chromosomes (gnomAD). c.274C>T has been reported in the literature in the compound heterozygous state in multiple individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Gunay-Aygun_2010, Xu_2014, Byun_2015/Jung_2020, Wicher_2020, Jayasinghe_2021, Ishiko_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19914852, 34536170, 32939031, 32384486, 33282801, 25153916). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Seven submitters classified the variant as pathogenic/likely pathogenic and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.