rs201105958

Positions:

chr6-52017512-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_138694.4(PKHD1):c.5498C>T(p.Ser1833Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:6

Conservation

PhyloP100: 2.06

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:

PKHD1 (HGNC:):

PKHD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-52017512-G-A is Pathogenic according to our data. Variant chr6-52017512-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 496898.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=1, Likely_pathogenic=5}. Variant chr6-52017512-G-A is described in Lovd as [Likely_pathogenic]. Variant chr6-52017512-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.40701413). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.5498C>T	p.Ser1833Leu	missense_variant	34/67	ENST00000371117.8	NP_619639.3	P08F94-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.5498C>T	p.Ser1833Leu	missense_variant	34/67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.5498C>T	p.Ser1833Leu	missense_variant	34/61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251130

Hom.:

AF XY:

0.000214

AC XY:

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000326

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000162

AC:

237

AN:

1461614

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

123

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.000281

Gnomad4 NFE exome

AF:

0.000190

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000188

Hom.:

Bravo

AF:

0.000140

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Pathogenic:4Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 23, 2018	The PKHD1 c.5498C>T (p.Ser1833Leu) missense variant has been reported in three studies and is found in three individuals with autosomal recessive polycystic kidney disease, two in a compound heterozygous state and one in whom zygosity was not specified, but who also carried two other variants (Rossetti et al. 2003; Gunay-Aygun et al. 2010; Tong et al. 2016). Probands exhibited phenotypes including medullary sponge kidney, Caroli's disease, and congenital hepatic fibrosis (Rossetti et al. 2003; Gunay-Aygun et al. 2010). Control data are unavailable for this variant, which is reported at a frequency of 0.000293 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Ser1833Leu variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 24, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Molecular Genetics, Children's Memorial Health Institute	Sep 25, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1833 of the PKHD1 protein (p.Ser1833Leu). This variant is present in population databases (rs201105958, gnomAD 0.03%). This missense change has been observed in individuals with polycystic kidney disease (PMID: 12846734, 19914852, 27752906, 33282801, 33940108, 35812281). ClinVar contains an entry for this variant (Variation ID: 496898). 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 not expected to disrupt PKHD1 protein function with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2023	Variant summary: PKHD1 c.5498C>T (p.Ser1833Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251130 control chromosomes (gnomAD). This frequency is not higher than estimated for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.00017 vs 0.0071), allowing no conclusion about variant significance. c.5498C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney And Hepatic Disease, and segregated with disease within families (e.g. Burgmaier_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likey pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1Uncertain:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2024	Observed phase unknown with a second variant in a patient with congenital hepatic fibrosis, Caroli's disease, and medullary sponge kidney in published literature (PMID: 12846734); 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: 26489027, 30809968, 14741187, 34405919, 33282801, 19914852, 27752906, 33940108, 35812281, 38051388, 12846734) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 28, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

PKHD1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 2024

The PKHD1 c.5498C>T variant is predicted to result in the amino acid substitution p.Ser1833Leu. This variant was reported with a second missense variant in an adult (38 years old) patient with cholangitis, medullary sponge kidney and cyst in a genetic study of patients with autosomal recessive polycystic kidney disease (ARPKD) (Rossetti et al. 2003. PubMed ID: 12846734). In addition, this variant was reported with a pathogenic (splice or exon-level deletion) variant in two unrelated families affected by ARPKD (Table S1 of Ajiri et al. 2022. PubMed ID: 35812281). Moreover, we have previously observed this variant together with a frameshift variant in two unrelated children tested for polycystic kidney disease at PreventionGenetics (internal data). This variant is reported in 0.030% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. Of note, this variant has been suggested to be incompletely penetrant (Mikó et al. 2021. PubMed ID: 34405919). -

Polycystic kidney disease 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;.

Eigen

Benign

-0.0065

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.080

MetaRNN

Benign

0.41

T;T

MetaSVM

Uncertain

0.013

MutationAssessor

Benign

1.9

L;L

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.058

T;T

Polyphen

0.98

D;D

Vest4

0.76

MVP

0.92

MPC

0.058

ClinPred

0.096

GERP RS

4.9

Varity_R

0.18

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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