Submissions for variant NM_138694.4(PKHD1):c.9308G>A (p.Gly3103Asp)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003313511	SCV004012425	likely pathogenic	not provided	2023-07-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30650191)
PreventionGenetics, part of Exact Sciences	RCV003395749	SCV004119879	likely pathogenic	PKHD1-related disorder	2023-04-27	criteria provided, single submitter	clinical testing	The PKHD1 c.9308G>A variant is predicted to result in the amino acid substitution p.Gly3103Asp. With a pathogenic PKHD1 frameshift variant c.353delG (p.S118Ifs*35), this missense variant has been reported in a prenatal case with isolated bilateral hyperechogenic kidneys, but the phase was unknown (Shuster et al. 2019. PubMed ID: 30650191). Of note, we have observed this variant previously at PreventionGenetics in an affected infant in trans with a well-documented pathogenic variant c.107C>T (p.Thr36Met). The p.Gly3103Asp variant is rare in the general population (https://gnomad.broadinstitute.org/variant/6-51613106-C-T). We interpret this variant as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479512	SCV004222713	uncertain significance	not specified	2023-11-15	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.9308G>A (p.Gly3103Asp) results in a non-conservative amino acid change located in the Right handed beta helix domain (IPR039448) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251136 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9308G>A has been reported in the literature in individuals affected with bilateral hyperchogenic kidneys (Shuster_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Polycystic Kidney And Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30650191). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV004572917	SCV005056292	likely pathogenic	Polycystic kidney disease 4	2024-03-10	criteria provided, single submitter	clinical testing