Submissions for variant NM_138694.4(PKHD1):c.9719G>A (p.Arg3240Gln)

dbSNP: rs146649803

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000694411	SCV000822856	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 3240 of the PKHD1 protein (p.Arg3240Gln). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 15698423, 19914852, 20413436, 24162162). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 572902). 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%. This variant disrupts the p.Arg3240 amino acid residue in PKHD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15805161). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000694411	SCV001137138	pathogenic	Autosomal recessive polycystic kidney disease	2019-05-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002493192	SCV002804351	pathogenic	Polycystic kidney disease 4	2022-01-14	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002493192	SCV003807195	pathogenic	Polycystic kidney disease 4	2022-07-22	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 moderated, PM2 moderated, PM3 strong, PP1 moderated
Lifecell International Pvt. Ltd	RCV002493192	SCV003924079	likely pathogenic	Polycystic kidney disease 4		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.9719G>A in Exon 58 of the PKHD1 gene that results in the amino acid substitution p.Arg3240Gln was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/Likely Pathogenic [Variation ID: 572902]. The observed variation has been observed in individual(s) with autosomal recessive polycystic kidney disease (Losekoot M, et.al., 2005). For these reasons, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV002493192	SCV004204537	pathogenic	Polycystic kidney disease 4	2023-09-19	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000694411	SCV002075536	pathogenic	Autosomal recessive polycystic kidney disease	2020-11-24	no assertion criteria provided	clinical testing