Submissions for variant NM_138694.4(PKHD1):c.12106C>T (p.Arg4036Trp)

gnomAD frequency: 0.00006  dbSNP: rs201210830

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000457190	SCV000545840	likely benign	Autosomal recessive polycystic kidney disease	2024-01-19	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000592520	SCV000700488	uncertain significance	not provided	2017-03-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193199	SCV001361900	uncertain significance	not specified	2020-11-09	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.12106C>T (p.Arg4036Trp) 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 7.6e-05 in 250920 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease (7.6e-05 vs 0.0071), allowing no conclusion about variant significance. However, the variant was also reported in Japanese healthy control databases (HGVD-Kyoto and jMorp) with a frequency of 0.006 (including 1 homozygote in HGVD-Kyoto database). This frequency is somewhat close to the estimated maximal expected allele frequency for a pathogenic PKHD1 variant, therefore this variant might represent a benign polymorphism found primarily in populations of East Asian origin (HGVD). To our knowledge, no occurrence of c.12106C>T in individuals affected with Polycystic Kidney and Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. Two other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV003243135	SCV003951790	likely benign	Inborn genetic diseases	2023-03-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000592520	SCV005042115	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	PKHD1: PM2, BP4
Natera, Inc.	RCV000457190	SCV002075457	uncertain significance	Autosomal recessive polycystic kidney disease	2018-11-06	no assertion criteria provided	clinical testing