NM_138694.4:c.8870T>C

Variant names:

• chr6-51753281-A-G
• rs760222236
• NM_138694.4:c.8870T>C

Variant summary

Our verdict is Pathogenic. The variant received 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:13
• Conservation: PhyloP100: 6.20
• Publications: 9 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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2414818.
• 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 VariationId is 357423.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.8870T>C	p.Ile2957Thr	missense_variant	Exon 57 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.8870T>C	p.Ile2957Thr	missense_variant	Exon 57 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.8870T>C	p.Ile2957Thr	missense_variant	Exon 57 of 61	5		ENSP00000341097.4

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

GnomAD2 exomes AF: 0.0000518 AC: 13 AN: 251136 AF XY: 0.0000590

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000846 AC: 94 AN: 1111756

Other (OTH) AF: 0.0000497 AC: 3 AN: 60378

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000798 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:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:5

May 09, 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 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. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 23, 2017

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.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. -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease 4 Pathogenic:3

Jan 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 4, with or without hepatic disease (MIM#263200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. There is significant intrafamilial variation of severity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (15 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change (p.(Ile2957Met)) has been reported as likely pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in compound heterozygous individuals with polycystic kidney disease, and once in an individual with congenital hepatic fibrosis (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKHD1: PM3:Very Strong, PM2 -

Apr 03, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Biliary tract abnormality Pathogenic:1

Sep 16, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

PKHD1-related disorder Pathogenic:1

Feb 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		6.2
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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs760222236; hg19: chr6-51618079;