Submissions for variant NM_138694.4(PKHD1):c.9925A>G (p.Ile3309Val)

gnomAD frequency: 0.00036  dbSNP: rs45627337

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000594183	SCV000703414	uncertain significance	not provided	2017-07-28	criteria provided, single submitter	clinical testing
Invitae	RCV000509311	SCV001197482	likely benign	Autosomal recessive polycystic kidney disease	2024-01-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000509311	SCV001323266	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470891	SCV002768830	uncertain significance	Polycystic kidney disease 4	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 4, with or without hepatic disease (MIM#263200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v3) for a recessive condition (52 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting (ClinVar). It has also been reported in one family and regarded as pathogenic, however the supporting evidence is insufficient (MyGene2). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV002527385	SCV003631387	uncertain significance	Inborn genetic diseases	2021-12-07	criteria provided, single submitter	clinical testing	The c.9925A>G (p.I3309V) alteration is located in exon 59 (coding exon 58) of the PKHD1 gene. This alteration results from a A to G substitution at nucleotide position 9925, causing the isoleucine (I) at amino acid position 3309 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV000594183	SCV003842655	uncertain significance	not provided	2022-09-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
GenomeConnect, ClinGen	RCV000509311	SCV000607188	not provided	Autosomal recessive polycystic kidney disease		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV000509311	SCV001453263	uncertain significance	Autosomal recessive polycystic kidney disease	2018-04-30	no assertion criteria provided	clinical testing
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844835	SCV001876988	uncertain significance	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research