Submissions for variant NM_138694.4(PKHD1):c.3467C>T (p.Ser1156Leu)

gnomAD frequency: 0.00004  dbSNP: rs367707903

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000788447	SCV000927563	likely pathogenic	not provided	2018-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004206	SCV001163051	likely pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Invitae	RCV001004206	SCV001198042	pathogenic	Autosomal recessive polycystic kidney disease	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1156 of the PKHD1 protein (p.Ser1156Leu). This variant is present in population databases (rs367707903, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 16199545, 20413436, 27225849, 33437033). 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: 636580). 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 with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV000788447	SCV001422382	likely pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001810487	SCV002060093	likely pathogenic	Polycystic kidney disease 4	2021-11-01	criteria provided, single submitter	clinical testing	NM_138694.3(PKHD1):c.3467C>T(S1156L) is a missense variant classified as likely pathogenic in the context of autosomal recessive polycystic kidney disease, PKHD1-related. S1156L has been observed in cases with relevant disease (PMID: 27225849, 27752906, 15698423, 19914852, 33940108, 33426401). Functional assessments of this variant are not available in the literature. S1156L has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_138694.3(PKHD1):c.3467C>T(S1156L) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Mendelics	RCV001810487	SCV002518868	pathogenic	Polycystic kidney disease 4	2022-05-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001810487	SCV002798983	likely pathogenic	Polycystic kidney disease 4	2022-05-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003396367	SCV004120136	likely pathogenic	PKHD1-related disorder	2023-05-01	criteria provided, single submitter	clinical testing	The PKHD1 c.3467C>T variant is predicted to result in the amino acid substitution p.Ser1156Leu. This variant has been reported in many individuals with autosomal recessive polycystic kidney disease (Bergmann et al 2005. PubMed ID: 15698423; Gunay-Aygun M et al 2009. PubMed ID: 19914852; Melchionda S et al 2016. PubMed ID: 27225849; Tong YQ et al 2016. PubMed ID: 27752906; Gately R et al 2020. PubMed ID: 33426401; Mallawaarachchi AC et al 2021. PubMed ID: 33437033; Burgmaier K et al 2021. PubMed ID: 33940108). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51893047-G-A). This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV001810487	SCV004204549	likely pathogenic	Polycystic kidney disease 4	2023-09-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001027935	SCV001190665	likely pathogenic	Polycystic kidney disease	2019-05-20	no assertion criteria provided	clinical testing
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844845	SCV001876963	uncertain significance	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research