rs199531851

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_138694.4(PKHD1):c.2414C>T(p.Pro805Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000701 in 1,611,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:5

Conservation

PhyloP100: 6.54

Variant links:

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

PKHD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.8

PP5

Variant 6-52046182-G-A is Pathogenic according to our data. Variant chr6-52046182-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377354.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=4, Pathogenic=2}. Variant chr6-52046182-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.2414C>T	p.Pro805Leu	missense_variant	Exon 24 of 67	ENST00000371117.8	NP_619639.3	P08F94-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 link	c.2414C>T	p.Pro805Leu	missense_variant	Exon 24 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.2414C>T	p.Pro805Leu	missense_variant	Exon 24 of 61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251210

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000733

AC:

107

AN:

1459020

Hom.:

Cov.:

AF XY:

0.0000647

AC XY:

AN XY:

726048

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000946

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000902

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:2

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 25, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM3, PP1, PP4, PP5 -

Jan 06, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 30507656, 30650191, 19940839, 18503009, 15108281, 16133180, 15698423, 12846734, 19914852, 15108277, 12506140) -

Aug 18, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PKHD1 c.2414C>T (p.Pro805Leu) variant causes a missense change involving a conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a "damaging" outcome, although these predictions have yet to be functionally assessed. This variant is not located in any known domain (InterPro, UniProt). The variant of interest was observed in the large broad control population from ExAC with an allele frequency of 7/121380 (0.0000575; 1/17340), which does not exceed the estimated maximal expected allele frequency for a pathogenic PKHD1 variant (0.0070711; 1/141). The variant of interest has been reported in multiple affected individuals in literature; however, all affected individuals have been found to carry another PKHD1 variant I3177T in the same allele. The complex p.[P805L;I3177T] is likely to be pathogenic based on family data but pathogenicity of p.P805L in isolation is unclear at this time. In a study, authors opine that the variant I3177T is the deleterious variant in the complex due to the fact that I3177T in isolation have been reported affected individuals whereas the p.P805L in isolation has yet to be reported in affected individuals. A clinical laboratory in 2012 reported the variant as pathogenic. Whether this variant is a modifier or a mild potentially pathogenic variant needs to be further studied by co-segregation and/or functional studies. Taken together, the variant of interest has currently been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available. -

Autosomal recessive polycystic kidney disease

Pathogenic:1Uncertain:1

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 805 of the PKHD1 protein (p.Pro805Leu). This variant is present in population databases (rs199531851, gnomAD 0.01%). This variant has been observed on the same chromosome with another PKHD1 variant (p.Ile3177Thr) in individuals affected with polycystic kidney disease (PMID: 16133180, 15108281, 18503009, 19940839). The haplotype (Pro805Leu; Ile3177Thr) has been observed on the opposite chromosome from other pathogenic variants in an individuals affected with polycystic kidney disease (PMID: 12846734, 15108281, Invitae). ClinVar contains an entry for this variant (Variation ID: 377354). 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%. 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. -

Polycystic kidney disease 4

Uncertain:2

Mar 27, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

0.41

MutationAssessor

Uncertain

2.9

M;M

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.93

P;P

Vest4

0.81

MVP

0.99

MPC

0.35

ClinPred

0.82

GERP RS

5.7

Varity_R

0.24

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over