Submissions for variant NM_138694.4(PKHD1):c.1736C>T (p.Thr579Met)

gnomAD frequency: 0.02436  dbSNP: rs45500692

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082531	SCV000114573	benign	not specified	2013-03-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000082531	SCV000315777	benign	not specified		criteria provided, single submitter	clinical testing
Invitae	RCV000468175	SCV000557657	benign	Autosomal recessive polycystic kidney disease	2024-02-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000468175	SCV000743918	benign	Autosomal recessive polycystic kidney disease	2014-10-09	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000468175	SCV000803552	benign	Autosomal recessive polycystic kidney disease	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Benign, for Polycystic kidney disease 4 with or without polycystic liver disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
Illumina Laboratory Services, Illumina	RCV000468175	SCV001320520	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Pars Genome Lab	RCV001530442	SCV001745270	benign	Polycystic kidney disease 4	2021-06-19	criteria provided, single submitter	clinical testing
GeneDx	RCV001719848	SCV001949052	benign	not provided	2020-10-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25701400)
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000468175	SCV000734509	benign	Autosomal recessive polycystic kidney disease		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292255	SCV001480890	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Thr579Met variant was identified in 8 of 1110 proband chromosomes (frequency: 0.007) from individuals or families with ADPKD and was present in 3 of 200 control chromosomes (frequency: 0.015) from healthy individuals (Sharp 2005, Losekoot 2005, Bergmann 2005, Edrees 2016, Obeidova 2015). The variant was also identified in dbSNP (ID: rs45500692) as “With Benign allele”, ClinVar (classified as benign by Invitae and Prevention Genetics), RWTH AAachen University ARPKD database (classified as polynorphism), databases. The variant was not identified in Genesight-COGR, LOVD 3.0, databases. The variant was identified in control databases in 6712 of 276722 chromosomes at a frequency of 0.024255 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Thr579 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein, in addition the variant amino acid Methionine (Met) is present in northern white cheeked gibbon, increasing the likelihood that this variant does not have clinical significance. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000082531	SCV002035505	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000468175	SCV002081065	benign	Autosomal recessive polycystic kidney disease	2017-05-11	no assertion criteria provided	clinical testing