rs760222236

chr6-51753281-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_138694.4(PKHD1):c.8870T>C(p.Ile2957Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000675 in 1,613,724 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2957M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 6.20

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr6-51753280-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2414818.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 6-51753281-A-G is Pathogenic according to our data. Variant chr6-51753281-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 357423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51753281-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.8870T>C	p.Ile2957Thr	missense_variant	57/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.8870T>C	p.Ile2957Thr	missense_variant	57/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.8870T>C	p.Ile2957Thr	missense_variant	57/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152184 Hom.: 0 Cov.: 33

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 251136 Hom.: 0 AF XY: 0.0000590 AC XY: 8 AN XY: 135702

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000677 AC: 99 AN: 1461540 Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 49 AN XY: 727076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000846

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74340

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: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 14, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2957 of the PKHD1 protein (p.Ile2957Thr). This variant is present in population databases (rs760222236, gnomAD 0.01%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 11898128, 11919560, 12506140, 15698423, 15805161, 19914852, 27225849). 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: 357423). 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%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 23, 2017	Variant summary: The PKHD1 c.8870T>C (p.Ile2957Thr) variant involves the alteration of a conserved nucleotide, which 3/4 in silico tools predict damaging outcome for this variant. This variant was found in 10/122220 control chromosomes at a frequency of 0.0000818, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). In literature, this variant is widely reported as a pathogenic variant and is found in several patients with autosomal recessive polycystic kidney disease with consistent genotype-phenotype evidences. Available patient data show that this variant is a severe mutation. A patient who carried 10627delT and p.I2957T variants was found to have no ARPKD protein (i.e. fibronectin), strongly suggesting that this variant leads to functional impairment (Ward_2003). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 14, 2018	A heterozygous missense variant, NM_138694.3(PKHD1):c.8870T>C, has been identified in exon 57 of 67 in the PKHD1 gene. The variant is predicted to result in a moderate amino acid change from an isoleucine to a threonine at position 2957 of the protein, NP_619639.3(PKHD1):p.(Ile2957Thr). The isoleucine residue at this position has moderate conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster) and the variant is present in the gnomAD database at a frequency of 0.0058% (16 heterozygotes, 0 homozygotes). However, the variant has been previously described as pathogenic in multiple individuals with autosomal recessive polycystic kidney disease (ClinVar, Ward et al., (2003)). Additionally, functional analysis compared fibrocystin in normal controls and a compound heterozygous patient (p.(Ile2957Thr) and a truncating variant). No fibrocystin was detected in the kidneys of this patient, suggesting a loss of protein function (Ward et al., (2003)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	Across nine studies, the PKHD1 c.8870T>C (p.Ile2957Thr) missense variant is reported in a total of 23 patients, including 19 compound heterozygotes with autosomal recessive polycystic kidney disease (ARPKD), one compound heterozygote with Caroli's disease and congenital hepatic fibrosis with minimal kidney involvement, two ARPKD patients carrying three variants in the PKHD1 gene, and one heterozygote in whom a second variant was not identified (Onuchic et al. 2002; Ward et al. 2002; Bergmann et al. 2003; Rossetti et al. 2003; Sharp et al. 2005; Gunay-Aygun et al. 2010; Denamur et al. 2010; Brinkert et al. 2013; Melchionda et al. 2016). Additionally, the p.Ile2957Thr variant was found in a heterozygous state in three unaffected family members of patients, and is noted to segregate in a manner consistent with recessive inheritance. The variant was absent from 360 control individuals and from at least 300 control chromosomes, but is reported at a frequency of 0.00013 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Ile2957Thr variant is classified as pathogenic for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Polycystic kidney disease 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 31, 2023	- -

Polycystic kidney disease Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKHD1 p.Ile2957Thr variant was identified in 15 of 690 proband chromosomes (frequency: 0.02) from individuals or families with ARPKD or congenital hepatic fibrosis and was not identified in 520 chromosomes from healthy individuals (Adeva 2006, Denamur 2010, Furu 2003, Gunay-Aygun 2010, Sharp 2005, Ward 2002). The variant was also identified in dbSNP (ID: rs760222236) “With Pathogenic allele”, ClinVar (classified pathogenic by Illumina Clinical Services Laboratory), RWTH AAachen University ARPKD database (classified pathogenic). The variant was also identified in control databases in 16 of 276840 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24028 chromosomes (freq: 0.00004), European Non-Finnish in 14 of 126434 chromosomes (freq: 0.0001), and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or European Finnish populations. The p.Ile2957 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Thr variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 02, 2023

Not observed at significant frequency in large population cohorts (gnomAD); 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: 20413436, 12846734, 19914852, 12874454, 15805161, 25701400, 15108281, 12506140, 27225849, 26385851, 11919560, 11898128, 19940839, 31980526, 32571524, 32574212, 31589614, 32939031) -

PKHD1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 02, 2024

The PKHD1 c.8870T>C variant is predicted to result in the amino acid substitution p.Ile2957Thr. This variant has been widely reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) (see for example, Ward et al. 2002. PubMed ID: 11919560; Obeidova et al. 2020. PubMed ID: 32574212; Table S2, Jayasinghe et al. 2021. PubMed ID: 32939031). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.7	H;H
MutationTaster	Benign	0.80	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.71
Sift	Benign	0.13	T;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;P
Vest4		0.78
MutPred		0.93		Gain of phosphorylation at I2957 (P = 0.0503);Gain of phosphorylation at I2957 (P = 0.0503);
MVP		0.99
MPC		0.40
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.37
gMVP		0.99

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

Other links and lift over

dbSNP: rs760222236; hg19: chr6-51618079;