Submissions for variant NM_138694.4(PKHD1):c.334G>A (p.Gly112Arg)

gnomAD frequency: 0.00039  dbSNP: rs149841071

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000595963	SCV000704700	uncertain significance	not provided	2017-12-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000671191	SCV000796143	uncertain significance	Autosomal recessive polycystic kidney disease	2017-12-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000671191	SCV000897305	uncertain significance	Autosomal recessive polycystic kidney disease	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000671191	SCV001413842	likely benign	Autosomal recessive polycystic kidney disease	2024-01-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290597	SCV001478686	uncertain significance	not specified	2021-01-11	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.334G>A (p.Gly112Arg) 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 0.00034 in 251404 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.00034 vs 0.0071), allowing no conclusion about variant significance. c.334G>A has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Bergmann_2005, Eisenberger_2015, Dafinger_2020). These reports do not provide unequivocal conclusions about association of the variant with Polycystic Kidney And Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000595963	SCV002568644	uncertain significance	not provided	2022-08-05	criteria provided, single submitter	clinical testing	Reported with additional PKHD1 variants (phase unknown) in a patient with polycystic kidney disease in published literature (Bergmann et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 25646624, 33112055, 15698423)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292159	SCV001480760	uncertain significance	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Gly112Arg variant was identified in 1 of 328 proband chromosomes (frequency: 0.003) from individuals or families with autosomal-recessive polycystic kidney disease (ARPKD; Bergmann 2005). The variant was also identified in dbSNP (ID: rs149841071) as N/A, LOVD 3.0, RWTH AAachen University ARPKD database (classified as pathogenic). The variant was not identified in ClinVar or GeneInsight-COGR databases. The variant was identified in control databases in 95 of 277140 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Gly112 residue is not 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 1 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. This variant is classified as a variant of uncertain significance.
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844839	SCV001876984	uncertain significance	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research
Natera, Inc.	RCV000671191	SCV002083415	uncertain significance	Autosomal recessive polycystic kidney disease	2018-05-22	no assertion criteria provided	clinical testing