Submissions for variant NM_138694.4(PKHD1):c.733C>T (p.Leu245=)

dbSNP: rs111809699

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082570	SCV000114612	benign	not specified	2015-08-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000082570	SCV000315825	benign	not specified	2016-03-21	criteria provided, single submitter	clinical testing
Invitae	RCV001081185	SCV000629931	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588255	SCV000699875	benign	not provided	2016-10-31	criteria provided, single submitter	clinical testing	Variant summary: The PKHD1 c.733C>T (p.Leu245Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant does not affect any ESE site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 629/121404 control chromosomes (16 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0566981 (590/10406). This frequency is about 8 times the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001081185	SCV001325969	benign	Autosomal recessive polycystic kidney disease	2017-09-29	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
GeneDx	RCV000588255	SCV001909256	benign	not provided	2018-07-14	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292393	SCV001480870	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Leu245= variant was not identified in the literature nor was it identified in the GeneInsight-COGR, LOVD 3.0, RWTH AAachen University ARPKD database, databases. The variant was also identified in dbSNP (ID: rs111809699) as With Benign allele, ClinVar (classified as benign by Invitae, and three clinical laboratories), Clinvitae, databases. The variant was identified in control databases in 1469 of 277116 chromosomes (37 homozygous) at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1337 of 24026 chromosomes (freq: 0.05), Other in 17 of 6466 chromosomes (freq: 0.003), Latino in 99 of 34416 chromosomes (freq: 0.003), European Non-Finnish in 13 of 126614 chromosomes (freq: 0.0001), and South Asian in 3 of 30782 chromosomes (freq: 0.0001), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, populations. The p.Leu245= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Natera, Inc.	RCV001081185	SCV002083393	benign	Autosomal recessive polycystic kidney disease	2017-05-11	no assertion criteria provided	clinical testing