Submissions for variant NM_138694.4(PKHD1):c.9215C>T (p.Ala3072Val)

gnomAD frequency: 0.00073  dbSNP: rs139306706

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000253968	SCV000114632	benign	not specified	2016-11-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000860694	SCV001000822	benign	Autosomal recessive polycystic kidney disease	2024-12-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000860694	SCV001319934	uncertain significance	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000253968	SCV001623230	benign	not specified	2021-05-09	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.9215C>T (p.Ala3072Val) results in a non-conservative amino acid change located in the Right handed beta helix domain (IPR039448) of 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 0.0021 in 251036 control chromosomes, predominantly at a frequency of 0.0086 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.2 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 South Asian origin. Although c.9215C>T has been reported in sequencing studies and databases (example, Bergmann_2005), to our knowledge, no occurrence of c.9215C>T in individuals affected with Polycystic Kidney And Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as benign.
Pars Genome Lab	RCV001449653	SCV001652869	likely benign	Polycystic kidney disease 4	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001705803	SCV001949051	benign	not provided	2020-08-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22995991, 15805161)
CeGaT Center for Human Genetics Tuebingen	RCV001705803	SCV005093489	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PKHD1: BP4, BS2
PreventionGenetics, part of Exact Sciences	RCV003891580	SCV000315851	benign	PKHD1-related disorder	2021-03-29	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001705803	SCV001932228	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001705803	SCV001969961	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000860694	SCV002077959	benign	Autosomal recessive polycystic kidney disease	2017-06-30	no assertion criteria provided	clinical testing