Submissions for variant NM_138694.4(PKHD1):c.1925C>T (p.Thr642Ile)

gnomAD frequency: 0.00070  dbSNP: rs138968608

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153724	SCV000203282	uncertain significance	not provided	2018-07-16	criteria provided, single submitter	clinical testing
Invitae	RCV001079254	SCV001002051	likely benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000153724	SCV002504291	uncertain significance	not provided	2022-03-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002516090	SCV003710847	likely benign	Inborn genetic diseases	2021-11-12	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.
PreventionGenetics, part of Exact Sciences	RCV003965145	SCV004785371	likely benign	PKHD1-related disorder	2022-02-07	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV001079254	SCV001463508	uncertain significance	Autosomal recessive polycystic kidney disease	2017-11-16	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV003150954	SCV003839877	uncertain significance	not specified	2022-08-26	no assertion criteria provided	clinical testing	DNA sequence analysis of the PKHD1 gene demonstrated a sequence change, c.1925C>T, in exon 20 that results in an amino acid change, p.Thr642Ile. This sequence change does not appear to have been previously described in individuals with PKHD1-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.26% in the African subpopulation and 0.026% in the overall population (dbSNP rs138968608). The p.Thr642Ile change affects a poorly conserved amino acid residue located in a domain of the PKHD1 protein that is not known to be functional. The p.Thr642Ile substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Thr642Ile change remains unknown at this time.