Submissions for variant NM_138694.4(PKHD1):c.2168G>T (p.Arg723Leu)

gnomAD frequency: 0.00029  dbSNP: rs150597050

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000591411	SCV000703433	benign	not specified	2016-11-10	criteria provided, single submitter	clinical testing
Invitae	RCV000860742	SCV001000884	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000860742	SCV001325522	uncertain significance	Autosomal recessive polycystic kidney disease	2018-01-12	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.
Genome-Nilou Lab	RCV001449937	SCV001653391	likely benign	Polycystic kidney disease 4	2021-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000591411	SCV002571033	likely benign	not specified	2022-07-12	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.2168G>T (p.Arg723Leu) results in a non-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 0.0015 in 250710 control chromosomes (gnomAD), predominantly at a frequency of 0.01 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.41 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.0071), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.2168G>T has been reported in the literature in one heterozygous individual affected with Polycystic Kidney Disease, however this individual also carried a different pathogenic variant in the PKD1 gene (c.6040C>T, p.Gln2014Ter) that was determined to be the cause of the patient's phenotype (Eisenberger_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as VUS, one as likely benign, and three as benign. Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV003431134	SCV004163602	benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	PKHD1: BP4, BS1, BS2
Natera, Inc.	RCV000860742	SCV001463504	benign	Autosomal recessive polycystic kidney disease	2019-12-17	no assertion criteria provided	clinical testing