Submissions for variant NM_138694.4(PKHD1):c.3686G>C (p.Trp1229Ser)

gnomAD frequency: 0.01066  dbSNP: rs2499481

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000177671	SCV000229575	benign	not specified	2015-02-23	criteria provided, single submitter	clinical testing
Invitae	RCV000231585	SCV000291331	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000177671	SCV000315797	benign	not specified		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000177671	SCV000699861	benign	not specified	2019-07-18	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.3686G>C (p.Trp1229Ser) results in a non-conservative amino acid change located in the IPT domain (IPR002909) 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 0.0034 in 280922 control chromosomes, predominantly at a frequency of 0.033 within the African or African-American subpopulation in the gnomAD database, including 18 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 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. The variant, c.3686G>C, has been reported in the literature in individuals affected with juvenile myoclonic epilepsy or Autosomal recessive polycystic kidney disease (Suzuki_2006, Melchionda_2016). 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. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) classified the variant as benign (2x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as benign.
Counsyl	RCV000231585	SCV000788695	likely benign	Autosomal recessive polycystic kidney disease	2017-01-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000231585	SCV001325407	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). 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	RCV001706138	SCV001897578	benign	not provided	2020-07-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16876319, 27225849)
CeGaT Center for Human Genetics Tuebingen	RCV001706138	SCV004699639	benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	PKHD1: BP4, BS1, BS2
Natera, Inc.	RCV000231585	SCV002080991	benign	Autosomal recessive polycystic kidney disease	2017-05-17	no assertion criteria provided	clinical testing