Submissions for variant NM_138694.4(PKHD1):c.275G>A (p.Arg92Gln)

gnomAD frequency: 0.00101  dbSNP: rs145886657

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000345554	SCV000464129	uncertain significance	Autosomal recessive polycystic kidney disease	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Eurofins Ntd Llc (ga)	RCV000598489	SCV000700533	uncertain significance	not provided	2018-08-03	criteria provided, single submitter	clinical testing
Invitae	RCV000345554	SCV001000715	likely benign	Autosomal recessive polycystic kidney disease	2024-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000598489	SCV001774345	uncertain significance	not provided	2023-08-02	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
PreventionGenetics, part of Exact Sciences	RCV003418077	SCV004118177	uncertain significance	PKHD1-related condition	2024-02-07	criteria provided, single submitter	clinical testing	The PKHD1 c.275G>A variant is predicted to result in the amino acid substitution p.Arg92Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of African descent in gnomAD. Of note, two different variants affecting the same amino acid residue (p.Arg92Gly and p.Arg92Trp) have been reported in ARPKD patients (Bergmann et al. 2005. PubMed ID: 15698423; Gunay-Aygun et al. 2010. PubMed ID: 19914852). In ClinVar, this variant is interpreted as likely benign/uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/357457/?new_evidence=true). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV000345554	SCV001453463	likely benign	Autosomal recessive polycystic kidney disease	2020-06-02	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000598489	SCV001553118	likely benign	not provided		no assertion criteria provided	clinical testing	The PKHD1 p.Arg92Gln variant was not identified in the literature nor was it identified in Cosmic or the RWTH AAachen University ARPKD database. The variant was identified in dbSNP (ID: rs145886657), ClinVar (classified as a VUS by Illumina and EGL Diagnostics for autosomal recessive polycystic kidney disease) and LOVD 3.0 (classified as likely benign by the VKGL data sharing initiative Nederland). The variant was identified in control databases in 184 of 282636 chromosomes (1 homozygous) at a frequency of 0.000651 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 30 of 24960 chromosomes (freq: 0.001202), European (non-Finnish) in 120 of 128986 chromosomes (freq: 0.00093), Other in 6 of 7214 chromosomes (freq: 0.000832), European (Finnish) in 16 of 25116 chromosomes (freq: 0.000637) and Latino in 12 of 35434 chromosomes (freq: 0.000339); it was not observed in the Ashkenazi Jewish, East Asian and South Asian populations. The p.Arg92 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, NNSPLICE, GeneSplicer) 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000598489	SCV002036336	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000598489	SCV002037758	likely benign	not provided		no assertion criteria provided	clinical testing