Submissions for variant NM_138694.4(PKHD1):c.8951-13C>T

gnomAD frequency: 0.00163  dbSNP: rs112249812

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781729	SCV000920000	uncertain significance	not specified	2020-11-02	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.8951-13C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 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 0.00037 in 243982 control chromosomes, predominantly at a frequency of 0.0054 within the African or African-American subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.0054 vs 0.0071), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.8951-13C>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 submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Illumina Laboratory Services, Illumina	RCV001158304	SCV001319935	uncertain significance	Autosomal recessive polycystic kidney disease	2018-01-13	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001158304	SCV001732610	benign	Autosomal recessive polycystic kidney disease	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001574413	SCV001801228	likely benign	not provided	2021-05-16	criteria provided, single submitter	clinical testing