Submissions for variant NM_138694.4(PKHD1):c.1877A>G (p.Lys626Arg)

gnomAD frequency: 0.00080  dbSNP: rs117122807

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169041	SCV000220199	benign	Autosomal recessive polycystic kidney disease	2014-03-27	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000176125	SCV000227727	benign	not specified	2015-04-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169041	SCV000557647	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000169041	SCV001325837	likely benign	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV001706102	SCV001873583	benign	not provided	2020-04-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30566001, 28814334, 28578020, 21790888)
CeGaT Center for Human Genetics Tuebingen	RCV001706102	SCV004810977	benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	PKHD1: BP4, BS1, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292486	SCV001481079	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Lys626Arg variant was identified in the literature in a case report of a 22 week fetus with findings consistent with ARPKD. Fetal genetic testing was declined, however the father was identified to carry the p.Lys626Arg variant but no additional suspicious variants were identified in the mother or father (Jang 2011). The variant was also identified in dbSNP (ID: rs117122807) “With Benign allele”, ClinVar (classified as benign by Counsyl and Emory Genetics), LOVD 3.0 (unclassified), and the RWTH AAachen University ARPKD database (unclassified) databases, but was not in the Geneinsight-COGR database. The variant was identified in control databases in 734 of 277024 chromosomes (10 homozygous) at a frequency of 0.00265 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Lys626Arg residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Natera, Inc.	RCV000169041	SCV002081059	benign	Autosomal recessive polycystic kidney disease	2017-05-11	no assertion criteria provided	clinical testing