Submissions for variant NM_138694.4(PKHD1):c.10684C>A (p.His3562Asn)

gnomAD frequency: 0.00016  dbSNP: rs140419956

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000276733	SCV000345855	uncertain significance	not provided	2018-01-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000309541	SCV000464034	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.
Fulgent Genetics, Fulgent Genetics	RCV002487293	SCV002787801	uncertain significance	Polycystic kidney disease 4	2021-12-02	criteria provided, single submitter	clinical testing
Invitae	RCV000309541	SCV003251577	uncertain significance	Autosomal recessive polycystic kidney disease	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 3562 of the PKHD1 protein (p.His3562Asn). This variant is present in population databases (rs140419956, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 291149). 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 not expected to disrupt PKHD1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002518161	SCV003731572	uncertain significance	Inborn genetic diseases	2021-06-22	criteria provided, single submitter	clinical testing	The c.10684C>A (p.H3562N) alteration is located in exon 61 (coding exon 60) of the PKHD1 gene. This alteration results from a C to A substitution at nucleotide position 10684, causing the histidine (H) at amino acid position 3562 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV000276733	SCV003918542	uncertain significance	not provided	2022-10-11	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; Has not been previously published as pathogenic or benign to our knowledge
Mayo Clinic Laboratories, Mayo Clinic	RCV000276733	SCV004227244	uncertain significance	not provided	2022-07-26	criteria provided, single submitter	clinical testing	PM2