6-52071009-T-C

Variant names:

• chr6-52071009-T-C
• rs369925690
• NM_138694.4:c.664A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM5 PP5_Very_Strong

The NM_138694.4(PKHD1):​c.664A>G​(p.Ile222Val) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,584,314 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I222L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25 O:1
• Conservation: PhyloP100: 4.44
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124901327 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_138694.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-52071009-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1371356.
• PP5: Variant 6-52071009-T-C is Pathogenic according to our data. Variant chr6-52071009-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 406891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.664A>G	p.Ile222Val	missense_variant	Exon 9 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.664A>G	p.Ile222Val	missense_variant	Exon 9 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.664A>G	p.Ile222Val	missense_variant	Exon 9 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152040 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000104 AC: 26 AN: 250892 AF XY: 0.0000959

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000106 AC: 152 AN: 1432274 Hom.: 0 Cov.: 27 AF XY: 0.000101 AC XY: 72 AN XY: 714758

African (AFR) AF: 0.00 AC: 0 AN: 32868

American (AMR) AF: 0.0000448 AC: 2 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.000423 AC: 11 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 85644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.000124 AC: 135 AN: 1085042

Other (OTH) AF: 0.0000673 AC: 4 AN: 59434

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152040 Hom.: 0 Cov.: 29 AF XY: 0.0000539 AC XY: 4 AN XY: 74256

African (AFR) AF: 0.0000241 AC: 1 AN: 41410

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68000

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000144 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:25 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:11 Other:1

Aug 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 222 of the PKHD1 protein (p.Ile222Val). This variant is present in population databases (rs369925690, gnomAD 0.05%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 11919560, 12506140, 12846734, 15698423, 19914852, 26695994). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 406891). 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. -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 26, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_138694.3(PKHD1):c.664A>G(I222V) is classified as pathogenic in the context of PKHD1-related, autosomal recessive polycystic kidney disease. Sources cited for classification include the following: PMID 19914852, 15698423, 12846734, 19940839, 11919560 and 12925574. Classification of NM_138694.3(PKHD1):c.664A>G(I222V) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 05, 2024

Gharavi Laboratory, Columbia University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

Compound heterozygote with NM_138694.4:c.2383C>T -

Feb 01, 2020

Molecular Biology Laboratory, Fundació Puigvert

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 01, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKHD1 c.664A>G (p.Ile222Val) missense variant has been reported in six studies and in a total of 18 individuals with autosomal recessive polycystic kidney disease, all in a compound heterozygous state (Ward et al. 2002; Onuchic et al. 2002; Rossetti et al. 2003; Bergmann et al. 2003; Gunay-Aygun et al. 2010; Brinkert et al. 2013). Segregation with disease has been shown in seven families (Ward et al. 2002; Onuchic et al. 2002; Rossetti et al. 2003; Bergmann et al. 2003; Gunay-Aygun et al. 2010). The p.Ile222Val variant was absent from 460 controls and is reported at a frequency of 0.000494 in the Ashkenazi Jewish population in the Genome Aggregation Database. Based on the collective evidence, the p.Ile2331Lys variant is classified as pathogenic for autosomal recessive polycystic disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

May 21, 2018

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variant, NM_138694.3(PKHD1):c.664A>G, has been identified in exon 9 of 67 of the PKHD1 gene. The variant is predicted to result in a minor amino acid change from isoleucine to valine at position 222 of the protein (NP_619639.3(PKHD1):p.(Ile222Val). The isoleucine residue at this position has very high conservation (100 vertebrates, UCSC), but is not located within any domains. In-silico predictions for this variant are consistently benign (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the database at a frequency of 0.01% (28/276558 heterozygotes and 0 homozygotes). The variant has been previously described as pathogenic in multiple patients with polycystic kidney disease (Onuchic, L. et al. 2002, Rosetti S. et al. 2003, Obeidova L. et al. 2015, Gunay-Aygun M. et al. 2010). It has also been shown to segregate with the disease in at least one family (Ward C. et al. 2002). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. The presence of these two variants suggests a possible compound heterozygous mode of inheritance which could be consistent with polycystic kidney disease. -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Ile222Val variant was identified in the compound heterozygous state by our study in one individual with autosomal recessive polycystic kidney disease. The p.Ile222Val variant is believed to be pathogenic based on numberous reports by other laboratories in the literature (Onuchic 2002, Bergmann 2005, Sharp 2005, Gunay-Aygun 2010). -

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GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as pathogenic and reported on 03/26/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Nov 23, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PKHD1 c.664A>G (p.Ile222Val) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 12/120972 control chromosomes at a frequency of 0.0000992, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). This variant has been reported in numerous ARPKD patients. Taken together, this variant is classified as pathogenic. -

Polycystic kidney disease 4 Pathogenic:8

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4 moderated, PM2 moderated, PM3 very strong -

Oct 01, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Apr 11, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 02, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11898128, 16133180, 30586318, 11919560, 15698423, 12506140, 26695994, 12846734, 20413436, 15805161, 25701400, 27225849, 30650191, 32574212, 34249099, 31589614, 32939031) -

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKHD1: PM3:Very Strong, PM2, PP4, BP4 -

Biliary tract abnormality Pathogenic:1

Apr 28, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases Pathogenic:1

Feb 04, 2024

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS3,PS4,PP4 -

PKHD1-related disorder Pathogenic:1

Oct 12, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKHD1 c.664A>G variant is predicted to result in the amino acid substitution p.Ile222Val. This variant has been repeatedly reported to be causative for autosomal recessive polycystic kidney disease (ARPKD) (Ward et al. 2002. PubMed ID: 11919560; Shuster et al. 2019. PubMed ID: 30650191; Obeidova et al. 2020. PubMed ID: 32574212; Jayasinghe et al. 2020. PubMed ID: 32939031). This variant is reported in 0.058% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51935807-T-C). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		4.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.57	N;N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.026	D;D
Polyphen		0.13	B;P
Vest4		0.84
MVP		0.92
MPC		0.080
ClinPred		0.16	T
GERP RS		5.2
Varity_R		0.33
gMVP		0.69
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs369925690; hg19: chr6-51935807;