Submissions for variant NM_138694.4(PKHD1):c.1964+17G>T

gnomAD frequency: 0.00517  dbSNP: rs201349527

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082532	SCV000114574	benign	not specified	2013-06-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588326	SCV000699852	uncertain significance	not provided	2016-08-01	criteria provided, single submitter	clinical testing	Variant summary: The PKHD1 c.1964+17G>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on the canonical splice donor site, but 4/5 splice prediction tools predict the gain of cryptic splice donor sites. ESEfinder predicts a gain of a binding motif for splicing enhancer SRp55. However, these predictions have yet to be confirmed by functional studies. This variant was found in 674/121292 control chromosomes (4 homozygotes), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0074681 (497/66550). This frequency is about 1.1 times the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this intronic variant may be a benign polymorphism found primarily in the non-Finnish Europeans. This variant was reported in at least one ARPKD patient without strong evidence for causality (Obeidova_BMC medical genetics_2015). In addition, one clinical diagnostic laboratory classified this variant as benign, without providing evidence to independently evaluate. Because of the limited clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS)-possibly benign until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001512862	SCV001720349	benign	Autosomal recessive polycystic kidney disease	2025-01-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588326	SCV004185361	likely benign	not provided	2025-02-01	criteria provided, single submitter	clinical testing	PKHD1: BS2
PreventionGenetics, part of Exact Sciences	RCV003891579	SCV000315780	benign	PKHD1-related disorder	2021-08-30	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).