Submissions for variant NM_138694.4(PKHD1):c.7482A>T (p.Gly2494=)

gnomAD frequency: 0.00001  dbSNP: rs199996156

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000383504	SCV000464064	likely benign	Autosomal recessive polycystic kidney disease	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780596	SCV000917996	benign	not specified	2018-10-12	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.7482A>T alters a 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 0.0015 in 277046 control chromosomes, predominantly at a frequency of 0.013 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2-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.7482A>T in individuals affected with Polycystic Kidney and Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV000383504	SCV001005276	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003932474	SCV004749418	benign	PKHD1-related disorder	2019-04-22	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292238	SCV001481069	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Gly2494= variant was not identified in the literature. The variant was identified in ClinVar (2 stars, classified as benign by Invitae and Integrated Genetics, likely benign by Illumina). The variant was identified in the dbSNP database (rs199996156). The variant was identified in control databases in 426 of 282704 chromosomes (2 homozygous) at a frequency of 0.001507, and was observed at the highest frequency in the South Asian population in 413 of 30600 chromosomes, at a frequency of 0.01350. (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Gly2494= variant does not alter the amino acid residue, and occurs outside of the splicing consensus sequence. In silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on 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.	RCV000383504	SCV002078022	likely benign	Autosomal recessive polycystic kidney disease	2017-05-11	no assertion criteria provided	clinical testing