Submissions for variant NM_138694.4(PKHD1):c.2507T>C (p.Val836Ala)

gnomAD frequency: 0.00002  dbSNP: rs199568593

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779513	SCV000916157	likely pathogenic	Autosomal recessive polycystic kidney disease	2018-12-05	criteria provided, single submitter	clinical testing	The PKHD1 c.2507T>C (p.Val836Ala) is a missense variant that has been reported in at least four studies in a compound heterozygous state in five individuals with autosomal recessive polycystic kidney disease (ARPKD) (Hao et al 2014; Liu et al. 2014; Kang et al. 2016; Cho et al. 2017). Hao et al. (2014) performed whole exome sequencing on 10 year-old male dizygotic twins with Caroli syndrome and identified the p.Val836Ala variant in a compound heterozygous state in both twins. Twin A had a more severe clinical presentation including liver cirrhosis, hypersplenism, and polycystic kidneys noted by age seven. Twin B had intrahepatic bile duct dilation, but otherwise no overt clinical symptoms. Liu et al. (2014) performed sequence analysis of the PKHD1 gene in three Chinese children with ARPKD. A seven year old boy with polycystic kidneys, bilateral enlargement of the kidneys, loss of corticomedullary differentiation, hepatosplenomegaly and portal hypertension, was found to be compound heterozygous for the p.Val836Ala variant with another missense variant. The p.Val836Ala variant was absent from 322 controls and is reported at a frequency of 0.001273 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Val836Ala variant is classified as likely pathogenic for the autosomal recessive form of polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Blueprint Genetics	RCV000788709	SCV000927915	pathogenic	not provided	2018-09-05	criteria provided, single submitter	clinical testing
Invitae	RCV000779513	SCV000950961	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 836 of the PKHD1 protein (p.Val836Ala). This variant is present in population databases (rs199568593, gnomAD 0.1%). This missense change has been observed in individual(s) with autosomal recessive cystic kidney disease and in combination with other rare variants in PKHD1 in several individuals affected with autosomal recessive cystic kidney disease (PMID: 24710345, 25124979, 27491411, 29643536). 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: 632491). 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%. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000779513	SCV001163054	likely pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001810485	SCV001427101	pathogenic	Polycystic kidney disease 4	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 4, with or without hepatic disease (MIM#263200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Significant intrafamilial variation of severity has been reported for this gene (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to alanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (21 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as compound heterozygous in multiple affected individuals (PMIDs: 24710345, 34536170, and VCGS), and as likely pathogenic/pathogenic many times in ClinVar. (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV000788709	SCV001818722	pathogenic	not provided	2023-04-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25124979, 28851938, 26385851, 29643536, 33123899, 35257483, 33569422, 31328266, 35314707, 24710345, 32939031, 34536170, 27491411)
Myriad Genetics, Inc.	RCV001810485	SCV002060071	likely pathogenic	Polycystic kidney disease 4	2021-10-20	criteria provided, single submitter	clinical testing	NM_138694.3(PKHD1):c.2507T>C(V836A) is a missense variant classified as likely pathogenic in the context of autosomal recessive polycystic kidney disease, PKHD1-related. V836A has been observed in cases with relevant disease (PMID: 24710345, 25124979, 27491411, 28851938, 29643536, 33123899, 33569422). Functional assessments of this variant are not available in the literature. V836A has been observed in population frequency databases (gnomAD: EAS 0.11%). In summary, NM_138694.3(PKHD1):c.2507T>C(V836A) 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.
Fulgent Genetics, Fulgent Genetics	RCV001810485	SCV002813346	likely pathogenic	Polycystic kidney disease 4	2022-03-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001810485	SCV003809378	likely pathogenic	Polycystic kidney disease 4	2022-05-13	criteria provided, single submitter	clinical testing
3billion	RCV001810485	SCV003842071	pathogenic	Polycystic kidney disease 4	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.85). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000632491). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 24710345, 34536170). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV001810485	SCV004204034	likely pathogenic	Polycystic kidney disease 4	2023-10-31	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000779513	SCV001463316	likely pathogenic	Autosomal recessive polycystic kidney disease	2020-09-16	no assertion criteria provided	clinical testing