Submissions for variant NM_138694.4(PKHD1):c.4130A>C (p.Asn1377Thr)

gnomAD frequency: 0.00001  dbSNP: rs773345692

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000263924	SCV000339758	uncertain significance	not provided	2016-02-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001158633	SCV001320284	uncertain significance	Autosomal recessive polycystic kidney disease	2018-01-12	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	RCV001158633	SCV003512631	uncertain significance	Autosomal recessive polycystic kidney disease	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with threonine at codon 1377 of the PKHD1 protein (p.Asn1377Thr). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and threonine. This variant is present in population databases (rs773345692, ExAC 0.001%). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 286356). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV002519230	SCV003540184	uncertain significance	Inborn genetic diseases	2022-09-14	criteria provided, single submitter	clinical testing	The c.4130A>C (p.N1377T) alteration is located in exon 32 (coding exon 31) of the PKHD1 gene. This alteration results from a A to C substitution at nucleotide position 4130, causing the asparagine (N) at amino acid position 1377 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.