Submissions for variant NM_138694.4(PKHD1):c.2279+13T>G

gnomAD frequency: 0.00572  dbSNP: rs188914598

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724186	SCV000227968	uncertain significance	not provided	2014-08-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000249026	SCV000315787	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001160100	SCV001321869	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.
Invitae	RCV001160100	SCV001719164	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000724186	SCV001818992	likely benign	not provided	2020-01-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000249026	SCV001983697	benign	not specified	2021-09-12	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.2279+13T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0058 in 251050 control chromosomes, predominantly at a frequency of 0.0091 within the Non-Finnish European subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.3 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 Non-Finnish European origin. To our knowledge, no occurrence of c.2279+13T>G 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. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000724186	SCV004163601	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	PKHD1: BS2
Natera, Inc.	RCV001160100	SCV002081037	benign	Autosomal recessive polycystic kidney disease	2018-04-16	no assertion criteria provided	clinical testing