Submissions for variant NM_138694.4(PKHD1):c.7873T>C (p.Leu2625=)

gnomAD frequency: 0.00001  dbSNP: rs140033417

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000250548	SCV000315833	likely benign	not specified		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000250548	SCV000917997	benign	not specified	2018-10-12	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.7873T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0031 in 277116 control chromosomes, predominantly at a frequency of 0.027 within the South Asian subpopulation in the gnomAD database, including 14 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease phenotype (0.0071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.7873T>C in individuals affected with Polycystic Kidney and Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV000863473	SCV001004141	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000863473	SCV001327303	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). 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	RCV001683132	SCV001905397	benign	not provided	2021-05-11	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292303	SCV001480582	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Leu2625= variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs140033417) as "With Likely benign allele", ClinVar (1x likely benign), and the RWTH AAachen University ARPKD database. The variant was also identified in control databases in 867 of 277116 chromosomes (16 homozygous) at a frequency of 0.003 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 2 of 24026 chromosomes (freq: 0.00008), Other in 13 of 6464 chromosomes (freq: 0.002), Latino in 2 of 34418 chromosomes (freq: 0.00006), European in 8 of 126612 chromosomes (freq: 0.00006), East Asian in 1 of 18870 chromosomes (freq: 0.00005), and South Asian in 841 of 30782 chromosomes (freq: 0.03). The variant was not observed in the Ashkenazi Jewish or Finnish, populations. The p.Leu2625= 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. In addition, 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.	RCV000863473	SCV002078006	benign	Autosomal recessive polycystic kidney disease	2017-05-11	no assertion criteria provided	clinical testing