Submissions for variant NM_138694.4(PKHD1):c.9619G>A (p.Ala3207Thr)

gnomAD frequency: 0.00001  dbSNP: rs1242089464

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814732	SCV000955154	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3207 of the PKHD1 protein (p.Ala3207Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of polycystic kidney disease (PMID: 19914852; Invitae). ClinVar contains an entry for this variant (Variation ID: 658007). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV001353367	SCV001548524	likely pathogenic	Polycystic kidney disease 4	2021-03-10	criteria provided, single submitter	clinical testing	This PKHD1 variant (rs1242089464) is rare (<0.1%) in a large population dataset (gnomAD: 1/251034 total alleles; 0.0004%; no homozygotes) and has an entry in ClinVar. It has been observed on the opposite chromosome from other pathogenic variants in individuals affected with PKD4. Three bioinformatics tools queried predict that p.Ala3207Thr would be damaging. The alanine residue at this position is strongly conserved across most vertebrate species assessed. This variant is not predicted to affect normal exon 58 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.9619G>A to be likely pathogenic.
GeneDx	RCV004702447	SCV005201629	likely pathogenic	not provided	2024-10-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 20413436, 19914852)
Fulgent Genetics, Fulgent Genetics	RCV001353367	SCV005670579	likely pathogenic	Polycystic kidney disease 4	2024-03-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000814732	SCV002077941	uncertain significance	Autosomal recessive polycystic kidney disease	2021-05-12	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748981	SCV005367186	uncertain significance	PKHD1-related disorder	2024-03-28	no assertion criteria provided	clinical testing	The PKHD1 c.9619G>A variant is predicted to result in the amino acid substitution p.Ala3207Thr. This variant has been reported in an individual with autosomal recessive polycystic kidney disease (ARPKD), and in two related individuals with ARPKD who also have another pathogenic missense variant (Gunay-Aygun et al 2010. PubMed ID: 19914852). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.