Submissions for variant NM_138694.4(PKHD1):c.3407A>G (p.Tyr1136Cys)

gnomAD frequency: 0.00885  dbSNP: rs41273726

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153718	SCV000203276	benign	not specified	2014-01-21	criteria provided, single submitter	clinical testing
Invitae	RCV000168029	SCV000218681	benign	Autosomal recessive polycystic kidney disease	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000168029	SCV000220206	likely benign	Autosomal recessive polycystic kidney disease	2014-03-30	criteria provided, single submitter	literature only
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224414	SCV000281491	likely benign	not provided	2015-02-06	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
PreventionGenetics, part of Exact Sciences	RCV000153718	SCV000315794	likely benign	not specified		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000224414	SCV000699860	likely benign	not provided	2017-06-19	criteria provided, single submitter	clinical testing	Variant summary: The PKHD1 c.3407A>G (p.Tyr1136Cys) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not available). This variant was found in 960/121796 control chromosomes (14 homozygotes) at a frequency of 0.007882, which slightly exceeds the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this variant is likely a benign polymorphism. In the literature this variant was reported in multiple patients with ARPKD without strong evidence for causality. One reported patient had co-occurrence of a pathogenic variant PKHD1 c. 1458C>A, p.Tyr486X in cis, supporting the non-pathgoenic nature of the variant of interest (Gunay-Aygun_MGM_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as a likely benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000168029	SCV000743915	likely benign	Autosomal recessive polycystic kidney disease	2016-12-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000168029	SCV001325726	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV001449932	SCV001653359	likely benign	Polycystic kidney disease 4	2021-05-18	criteria provided, single submitter	clinical testing
Laboratory of Molecular Diagnosis of Genetic Disease, Università degli Studi di Napoli Federico II	RCV001507102	SCV001712073	uncertain significance	Caroli disease	2021-05-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000224414	SCV001883125	benign	not provided	2020-12-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30343465, 15805161, 21228398)
CeGaT Center for Human Genetics Tuebingen	RCV000224414	SCV002563899	benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	PKHD1: BP4, BS1, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001291851	SCV000592891	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Tyr1136Cys variant was identified in 1 of 450 proband chromosomes (frequency: 0.002) from individuals or families with ARPKD, and was present in 1 of 400 control chromosomes (frequency: 0.0025) from healthy individuals (Bergmann_2005, Losekoot_2005). The variant was identified in dbSNP (ID: rs41273726) with “other” allele, in the 1000 Genomes Project in 13 of 5000 chromosomes (frequency: 0.0026) and in Exome Variant Server project in 88 of 8600 (frequency 0.01) in European American alleles and 3 of 4406 (frequency 0.0007) African American alleles. The variant was also identified in the Exome Aggregation Consortium database (March 14, 2016) in 959 of 121396 chromosomes of which 14 are homozygotes (frequency 0.0079); or 80 of 6612 European Finnish (frequency 0.0121), 797 of 66734 European non Finnish (frequency 0.01194), 37 of 16512 south Asians (frequency 0.002241), 22 of 11576 Latino (frequency 0.0019), 15 of 10404 African (frequency 0.01442), 1 of 8650 East Asians (frequency 0.0001) and 7 of 908 other (frequency 0.008). The variant was also listed in ClinVar 1x by Emory Genetics Laboratory and 1x by Invitae as benign and identified by Counsyl 1x as likely benign and in Clinvitae by EmyClass 1x as benign. The variant was also identified in RWTH AAachen University ARPKD database with conflicting interpretations: 6x as polymorphism, 11x as pathogenic and 13x as probably pathogenic with control frequency of 0% - 0.5%. The p.Tyr1136 residue is not entirely conserved in mammals and the variant amino acid Cystine is present in frog 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. In addition this variant was seen co-occurring with a pathogenic variant (c.8095C>T, p.Gln2699X) in a patient with polycystic kidney disease. 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 likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000168029	SCV000734507	likely benign	Autosomal recessive polycystic kidney disease		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000224414	SCV002036869	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000168029	SCV002080997	likely benign	Autosomal recessive polycystic kidney disease	2017-03-28	no assertion criteria provided	clinical testing