Submissions for variant NM_138694.4(PKHD1):c.4009G>A (p.Asp1337Asn)

gnomAD frequency: 0.00008  dbSNP: rs373255125

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000264443	SCV000342583	uncertain significance	not provided	2018-01-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000374359	SCV000464087	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.
Invitae	RCV000374359	SCV002394741	likely benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470838	SCV002768832	uncertain significance	Polycystic kidney disease 4	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3C-VUS. 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) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (32 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2) (7 heterozygotes, 1 homozygote). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated atypical IPT/TIG 8 domain (PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as VUS in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV000264443	SCV004170355	uncertain significance	not provided	2023-04-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36387797)
PreventionGenetics, part of Exact Sciences	RCV003949917	SCV004762078	uncertain significance	PKHD1-related condition	2024-02-16	criteria provided, single submitter	clinical testing	The PKHD1 c.4009G>A variant is predicted to result in the amino acid substitution p.Asp1337Asn. This variant, along with a PKD1 missense variant, has been reported with uncertain significance in a an individual with autosomal dominant polycystic kidney disease; however, both variants were also reported in an unaffected family member (Table 1, Zhou L et al. 2022. PubMed ID: 36387797). This variant has also been reported with uncertain significance in the compound heterozygous state with another PKHD1 missense variant, in an individual who was later found to have a pathogenic EYA1 variant (Abstract# ACPN210331P47, Lin Z et al. 2021. PubMed ID: 34106318). This variant is reported in 0.10% of alleles in individuals of East Asian descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.