Submissions for variant NM_138694.4(PKHD1):c.9705T>A (p.Asn3235Lys)

dbSNP: rs759568939

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000265753	SCV000464039	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.
Counsyl	RCV000265753	SCV000790717	uncertain significance	Autosomal recessive polycystic kidney disease	2017-04-05	criteria provided, single submitter	clinical testing
Invitae	RCV000265753	SCV001232187	likely benign	Autosomal recessive polycystic kidney disease	2024-01-29	criteria provided, single submitter	clinical testing
Pars Genome Lab	RCV001526423	SCV001736783	uncertain significance	Polycystic kidney disease 4	2021-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001526423	SCV001806438	uncertain significance	Polycystic kidney disease 4	2021-07-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001526423	SCV002769166	uncertain significance	Polycystic kidney disease 4	2019-08-28	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_138694.3(PKHD1):c.9705T>A in exon 58 of 67 of the PKHD1 gene. This substitution is predicted to create a moderate amino acid change from asparagine to lysine at position 3235 of the protein, NP_619639.3(PKHD1):p.(Asn3235Lys). The asparagine at this position has moderate conservation (100 vertebrates, UCSC), but is not situated in a known functional domain. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.015% (35 heterozygotes, 1 homozygote). The variant has been previously reported as both a VUS (ClinVar) and in a homozygote patient with polycystic kidney disease (Alehabib, E., et al. (2017)). Subsequent analysis of parental samples indicated this variant was maternally inherited. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS).
Natera, Inc.	RCV000265753	SCV002075537	uncertain significance	Autosomal recessive polycystic kidney disease	2018-07-17	no assertion criteria provided	clinical testing