Submissions for variant NM_138694.4(PKHD1):c.1342G>C (p.Gly448Arg)

gnomAD frequency: 0.00146  dbSNP: rs149781976

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000415990	SCV000493239	uncertain significance	not provided	2016-10-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000415990	SCV000704763	uncertain significance	not provided	2018-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000669988	SCV000794795	uncertain significance	Autosomal recessive polycystic kidney disease	2017-10-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000669988	SCV000897302	uncertain significance	Autosomal recessive polycystic kidney disease	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000669988	SCV001000747	likely benign	Autosomal recessive polycystic kidney disease	2024-11-05	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000415990	SCV001251895	uncertain significance	not provided	2020-05-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000669988	SCV001321980	uncertain significance	Autosomal recessive polycystic kidney disease	2017-04-27	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000415990	SCV001803854	likely benign	not provided	2021-02-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29642553, 25646624, 28492530, 26489027, 15805161, 21228398, 15698423)
Natera, Inc.	RCV000669988	SCV001463515	uncertain significance	Autosomal recessive polycystic kidney disease	2017-05-08	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000415990	SCV001551478	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PKHD1 p.Gly448Arg variant was identified in 4 of 618 proband chromosomes (frequency: 0.0065) from individuals with polycystic kidney disease (Eisenberger_2015_PMID:25646624; Bergmann_2005_PMID:15698423; Vora_2017_PMID:28518170; Sharp_2005_PMID:15805161). The variant was identified in dbSNP (ID: rs149781976), LOVD 3.0, ClinVar (classified as uncertain significance by EGL genetics, CeGaT Praxis fuer Humangenetik Tuebingen, Fulgent Genetics and Counsyl for autosomal recessive polycystic kidney disease, and as likely benign by Invitae) and the RWTH AAachen University ARPKD database. The variant was identified in control databases in 445 of 282546 chromosomes at a frequency of 0.001575 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 330 of 128880 chromosomes (freq: 0.002561), Other in 14 of 7220 chromosomes (freq: 0.001939), Latino in 54 of 35432 chromosomes (freq: 0.001524), European (Finnish) in 19 of 25122 chromosomes (freq: 0.000756), South Asian in 16 of 30616 chromosomes (freq: 0.000523), African in 11 of 24968 chromosomes (freq: 0.000441) and Ashkenazi Jewish in 1 of 10358 chromosomes (freq: 0.000097), but was not observed in the East Asian population. The p.Gly448 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844830	SCV001876964	uncertain significance	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000415990	SCV002034935	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000415990	SCV002035961	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003922678	SCV004738288	likely benign	PKHD1-related disorder	2024-09-25	no assertion criteria provided	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).