Submissions for variant NM_138694.4(PKHD1):c.4199C>T (p.Ser1400Leu)

gnomAD frequency: 0.00002  dbSNP: rs191201723

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000529518	SCV000629918	uncertain significance	Autosomal recessive polycystic kidney disease	2021-08-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine with leucine at codon 1400 of the PKHD1 protein (p.Ser1400Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs191201723, ExAC 0.01%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 27225849). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Counsyl	RCV000529518	SCV000789848	uncertain significance	Autosomal recessive polycystic kidney disease	2017-02-23	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000733218	SCV000861255	uncertain significance	not provided	2018-05-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000529518	SCV001320283	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000529518	SCV001427106	likely pathogenic	Autosomal recessive polycystic kidney disease	2018-05-14	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_138694.3(PKHD1):c.4199C>T, has been identified in exon 32 of 67 in the PKHD1 gene. The variant is predicted to result in a major amino acid change from a serine to a leucine at position 1400 of the protein, NP_619639.3(PKHD1):p.(Ser1400Leu). The serine residue at this position has low conservation (100 vertebrates, UCSC), however is located within the IPT functional domain. In silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.0024% (6 heterozygotes, 0 homozygotes) and has been previously described as a VUS in an individual with polycystic kidney disease, however a second variant was not identified in that individual (ClinVar). Parental testing has indicated this variant is in trans with c.8870T>C. Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. NB: This variant has been reclassified to likely pathogenic due to compound heterozygous inheritance.
Baylor Genetics	RCV003476228	SCV004202272	likely pathogenic	Polycystic kidney disease 4	2023-09-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000529518	SCV002080962	uncertain significance	Autosomal recessive polycystic kidney disease	2018-05-29	no assertion criteria provided	clinical testing