Submissions for variant NM_138694.4(PKHD1):c.11525G>T (p.Arg3842Leu)

dbSNP: rs76572975

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082521	SCV000114563	benign	not specified	2013-07-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000082521	SCV000315763	benign	not specified		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079886	SCV000557643	benign	Autosomal recessive polycystic kidney disease	2025-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587495	SCV000699846	benign	not provided	2016-12-12	criteria provided, single submitter	clinical testing	Variant summary: The PKHD1 c.11525G>T (p.Arg3842Leu) variant causes a missense change involving a non-conserved nucleotide, which in silico tools predict conflicting results, 2/4 predict "benign" and 2/4 predict "damaging." This variant was found in 2160/121714 control chromosomes (including 21 homozygotes) at a frequency of 0.0177465, which is approximately 3 times the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this variant is likely a benign polymorphism. The variant is more common in European subpopulations from ExAC with allele frequencies of 3-4%. In literature, the variant has also been reported as a polymorphism or a benign variant found in ARPKD patients (Bergmann_2005, Sharp_2005, Gunay-Aygun_2010). In addition, multiple clinical diagnostic laboratories have classified this variant as benign. Taken together, this variant is classified as Benign.
Illumina Laboratory Services, Illumina	RCV001079886	SCV001323137	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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
GeneDx	RCV000587495	SCV001934765	benign	not provided	2020-10-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15698423, 19914852)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292514	SCV001480647	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Arg3842Leu variant was identified in 8 of 636 proband chromosomes (frequency: 0.01) from European, Dutch and American individuals or families with ARPKD and was present in 11 of 600 control chromosomes (frequency: 0.02) from healthy individuals (Sharp_2005_15805161, Losekoot_2005_16133180, Gunay-Aygun_2010_19914852, Bergmann_2005_15698423). The variant was also identified in the following databases: dbSNP (ID: rs76572975) “With Benign allele”, ClinVar (benign by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), Prevention Genetics and Invitae), RWTH AAachen University ARPKD database, and was not identified in the COGR and LOVD 3.0. The variant was identified in control databases in 5207 (73 homozygous) of 276514 chromosomes at a frequency of 0.02 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 77 of 24014 chromosomes (freq: 0.003), Other in 113 (2 homozygous) of 6444 chromosomes (freq: 0.02), Latino in 402 (4 homozygous) of 34320 chromosomes (freq: 0.01), European Non-Finnish in 3049 (41 homozygous) of 126226 chromosomes (freq: 0.02), Ashkenazi Jewish in 241 (3 homozygous) of 10130 chromosomes (freq: 0.02), European Finnish in 1066 (23 homozygous) of 25770 chromosomes (freq: 0.04), and South Asian in 259 of 30778 chromosomes (freq: 0.008); it was not observed in the East Asian populations. The p.Arg3842 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Leu 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, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000587495	SCV001799915	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000082521	SCV001933020	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001079886	SCV002075476	benign	Autosomal recessive polycystic kidney disease	2017-05-11	no assertion criteria provided	clinical testing