rs370277502

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The ENST00000371117.8(PKHD1):c.274C>T(p.Arg92Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,956 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R92Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PKHD1
ENST00000371117.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10U:1

Conservation

PhyloP100: 2.36

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 Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.759

PP5

Variant 6-52082399-G-A is Pathogenic according to our data. Variant chr6-52082399-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 286684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52082399-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.274C>T	p.Arg92Trp	missense_variant	4/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.274C>T	p.Arg92Trp	missense_variant	4/67	1	NM_138694.4	ENSP00000360158	P2	P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.274C>T	p.Arg92Trp	missense_variant	4/61	5		ENSP00000341097	A2	P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251230

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461758

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74396

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:

0.0000294

Gnomad4 OTH

AF:

0.00

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Nov 23, 2018	A heterozygous missense variant, NM_138694.3(PKHD1):c.274C>T, has been identified in exon 4 of 67 of the PKHD1 gene. The variant is predicted to result in a major amino acid change from arginine to tryptophan at position 92 of the protein (NP_619639.3(PKHD1):p.(Arg92Trp)). The arginine residue at this position has low conservation (100 vertebrates, UCSC), and 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 0.001% (3 heterozygotes, 0 homozygotes). An alternative residue change, p.(Arg92Gln) has been reported in the gnomAD database at a frequency of 0.07% (182 heterozygotes, 1 homozygote). The p.(Arg92Trp) variant has been previously described as pathogenic and segregated with disease in multiple families with Polycystic kidney disease (ClinVar, Gunay-Aygun, M. et al. (2010), Xu, Y. et al. (2014), Byun, YJ. et al. (2015), Schueler, M. et al (2016), PKHD1 Database). A different variant affecting the same amino acid resulting in a change to glycine has also been shown to cause Polycystic kidney disease (Bergmann, C. et al. (2005)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 14, 2023	Variant summary: PKHD1 c.274C>T (p.Arg92Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251230 control chromosomes (gnomAD). c.274C>T has been reported in the literature in the compound heterozygous state in multiple individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Gunay-Aygun_2010, Xu_2014, Byun_2015/Jung_2020, Wicher_2020, Jayasinghe_2021, Ishiko_2022). 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. The following publications have been ascertained in the context of this evaluation (PMID: 19914852, 34536170, 32939031, 32384486, 33282801, 25153916). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Seven submitters classified the variant as pathogenic/likely pathogenic and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 20, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 92 of the PKHD1 protein (p.Arg92Trp). This variant is present in population databases (rs370277502, gnomAD 0.007%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 19914852, 25153916, 32384486, 32939031, 33123899). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 286684). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PKHD1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Polycystic kidney disease 4

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 19, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Protein truncation variants are a common disease-causing mechanism. In silico tools do not predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.01). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000286684). A different missense change at the same codon (p.Arg92Gly) has been reported to be associated with PKHD1 related disorder (PMID: 15698423). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Mar 28, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: Byun_2015_article, 30275481, 32939031, 19914852, 32384486, 25153916, 33282801) -

PKHD1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 03, 2023

The PKHD1 c.274C>T variant is predicted to result in the amino acid substitution p.Arg92Trp. This variant alongside a pathogenic truncating PKHD1 variant has been reported in multiple individuals with autosomal recessive polycystic kidney disease (ARPKD) (Gunay-Aygun et al. 2010. PubMed ID: 19914852; Table S3, Jayasinghe et al. 2020. PubMed ID: 32939031; Jung et al. 2020. PubMed ID: 32384486). This variant has also been reported with another suspected pathogenic PKHD1 variant in a Chinese family with autosomal recessive polycystic kidney disease (ARPKD) (Xu et al. 2014. PubMed ID: 25153916). Of note, a different substitution at the same codon (p.Arg92Gly) has been reported in a patient with ARPKD (Bergmann et al. 2005. PubMed ID: 15698423). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51947197-G-A). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

T;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Benign

-0.31

MutationAssessor

Benign

1.6

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-2.1

N;N

REVEL

Uncertain

0.46

Sift

Uncertain

0.0070

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.53

MVP

0.98

MPC

0.35

ClinPred

0.83

GERP RS

4.6

Varity_R

0.080

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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