Submissions for variant NM_138694.4(PKHD1):c.10585G>C (p.Glu3529Gln)

gnomAD frequency: 0.01187  dbSNP: rs145184792

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082516	SCV000114558	benign	not specified	2015-08-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000169285	SCV000220595	likely benign	Autosomal recessive polycystic kidney disease	2014-08-13	criteria provided, single submitter	literature only
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224832	SCV000281593	likely benign	not provided	2015-07-08	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169285	SCV000291323	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000082516	SCV000315756	likely benign	not specified		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000082516	SCV000699842	benign	not specified	2020-08-07	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.10585G>C (p.Glu3529Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0039 in 281654 control chromosomes, predominantly at a frequency of 0.038 within the African or African-American subpopulation in the gnomAD database (v2.1), including 21 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease phenotype (0.0071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.10585G>C has been reported in the literature in an individual affected with Polycystic Kidney and Hepatic Disease (Rossetti_2003). This report however does not provide unequivocal conclusions about association of the variant with Polycystic Kidney and Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (4x) / likely benign (1x). Based on the evidence outlined above, the variant was classified as benign.
SIB Swiss Institute of Bioinformatics	RCV000169285	SCV000803524	benign	Autosomal recessive polycystic kidney disease	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Benign, for Polycystic kidney disease 4 with or without polycystic liver disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
Illumina Laboratory Services, Illumina	RCV000169285	SCV001321744	benign	Autosomal recessive polycystic kidney disease	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
GeneDx	RCV000224832	SCV001949049	benign	not provided	2019-10-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22995991, 21228398, 12846734, 27884173, 26990548, 24984783)
Breakthrough Genomics, Breakthrough Genomics	RCV000224832	SCV005226120	likely benign	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000169285	SCV002075506	benign	Autosomal recessive polycystic kidney disease	2017-06-30	no assertion criteria provided	clinical testing