6-52071009-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 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:21 O:1
• Conservation: PhyloP100: 4.44

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]

LOC124901327 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_138694.4
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 1371356.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP5: Variant 6-52071009-T-C is Pathogenic according to our data. Variant chr6-52071009-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52071009-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.664A>G	p.Ile222Val	missense_variant	9/67	ENST00000371117.8
LOC124901327	XR_007059606.1	n.7T>C		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.664A>G	p.Ile222Val	missense_variant	9/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.664A>G	p.Ile222Val	missense_variant	9/61	5		A2

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

GnomAD3 exomes AF: 0.000104 AC: 26 AN: 250892 Hom.: 0 AF XY: 0.0000959 AC XY: 13 AN XY: 135566

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.000423

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000124

Gnomad4 OTH exome AF: 0.0000673

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

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000105 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:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:10 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 23, 2016	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. -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 01, 2018	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. -
Likely pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 26, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	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. -

Polycystic kidney disease 4 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 20, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Apr 25, 2022	ACMG classification criteria: PS4 moderated, PM2 moderated, PM3 very strong -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	PKHD1: PM3:Very Strong, PM2, PP4, BP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Apr 11, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2023	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) -
Pathogenic, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Feb 04, 2024

ACMG categories: PS3,PS4,PP4 -

PKHD1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 12, 2023

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
MutationTaster	Benign	0.80	N;N
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

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs369925690; hg19: chr6-51935807;