Submissions for variant NM_138694.4(PKHD1):c.7942G>A (p.Gly2648Ser)

gnomAD frequency: 0.00158  dbSNP: rs139555370

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082577	SCV000114619	benign	not specified	2015-03-11	criteria provided, single submitter	clinical testing
Invitae	RCV000233605	SCV000291340	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000082577	SCV000315835	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000233605	SCV001327301	benign	Autosomal recessive polycystic kidney disease	2017-04-27	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
GeneDx	RCV001650934	SCV001870900	benign	not provided	2020-03-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16876319, 24162162)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000082577	SCV002571031	benign	not specified	2022-07-13	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.7942G>A (p.Gly2648Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0056 in 251260 control chromosomes (gnomAD), predominantly at a frequency of 0.036 within the Latino subpopulation in the gnomAD database, including 21 homozygotes. The observed variant frequency within Latino 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 Latino origin. c.7942G>A has been reported in the literature in at least two heterozygous individuals affected with Polycystic Kidney Disease, however without strong evidence for causality (e.g.Krall_2014, Hu_2021). Therefore, these reports do 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 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Fulgent Genetics, Fulgent Genetics	RCV002498435	SCV002804591	benign	Polycystic kidney disease 4	2022-04-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000233605	SCV002078003	benign	Autosomal recessive polycystic kidney disease	2017-05-16	no assertion criteria provided	clinical testing