Submissions for variant NM_138694.4(PKHD1):c.2279G>A (p.Arg760His)

gnomAD frequency: 0.00001  dbSNP: rs745770404

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169230	SCV000220499	likely pathogenic	Autosomal recessive polycystic kidney disease	2014-07-11	criteria provided, single submitter	literature only
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000169230	SCV000786708	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	research	The heterozygous p.Arg760His variant was identified in the compound heterozygous state by our study in one individual with autosomal recessive polycystic kidney disease. The p.Arg760His variant is believed to be pathogenic based on numberous reports by other laboratories in the literature (Onuchic 2002, Bergmann 2005, Sharp 2005, Gunay-Aygun 2010).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169230	SCV001415899	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 760 of the PKHD1 protein (p.Arg760His). This variant also falls at the last nucleotide of exon 22, which is part of the consensus splice site for this exon. This variant is present in population databases (rs745770404, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 11898128, 15698423, 20413436). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188876). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24984783). For these reasons, this variant has been classified as Pathogenic.
Molecular Biology Laboratory, Fundació Puigvert	RCV000169230	SCV001425225	likely pathogenic	Autosomal recessive polycystic kidney disease	2020-02-01	criteria provided, single submitter	research
Baylor Genetics	RCV001283774	SCV001523795	pathogenic	Polycystic kidney disease 4	2024-03-21	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001283774	SCV004807325	pathogenic	Polycystic kidney disease 4	2024-03-26	criteria provided, single submitter	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV001283774	SCV001469147	pathogenic	Polycystic kidney disease 4	2020-09-10	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169230	SCV002081038	pathogenic	Autosomal recessive polycystic kidney disease	2018-07-28	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003927564	SCV004739853	pathogenic	PKHD1-related disorder	2024-05-06	no assertion criteria provided	clinical testing	The PKHD1 c.2279G>A variant is predicted to result in the amino acid substitution p.Arg760His. This substitution occurs at the last nucleotide of exon 22 and is predicted to substantially affect normal splicing by available splicing prediction programs (Alamut Visual Plus v1.6.1). This variant has been reported in individuals with autosomal recessive polycystic kidney disease (ARPKD) (Onuchic et al. 2002. PubMed ID: 11898128; Jordan et al. 2022. PubMed ID: 35005812). Of note, we have previously observed this variant at PreventionGenetics in the homozygous state in an affected child and the heterozygous state in other PKD patients who have another pathogenic PKHD1 variant. The c.2279G>A variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.