rs200511261

Variant names:

• chr6-51748086-A-G
• rs200511261
• NM_138694.4:c.9530T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP5

The NM_138694.4(PKHD1):​c.9530T>C​(p.Ile3177Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000917 in 1,613,662 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I3177V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:4
• Conservation: PhyloP100: 6.10
• Publications: 6 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: Uncertain_significance. The variant received 3 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, 8 uncertain in NM_138694.4
• PP5: Variant 6-51748086-A-G is Pathogenic according to our data. Variant chr6-51748086-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 377018.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.9530T>C	p.Ile3177Thr	missense_variant	Exon 58 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.9530T>C	p.Ile3177Thr	missense_variant	Exon 58 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.9530T>C	p.Ile3177Thr	missense_variant	Exon 58 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152216 Hom.: 0 Cov.: 32

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000518 AC: 13 AN: 250878 AF XY: 0.0000369

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: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000965 AC: 141 AN: 1461446 Hom.: 0 Cov.: 33 AF XY: 0.0000825 AC XY: 60 AN XY: 727056

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000125 AC: 139 AN: 1111634

Other (OTH) AF: 0.0000331 AC: 2 AN: 60386

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74378

African (AFR) AF: 0.0000241 AC: 1 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000833 Hom.: 0

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Uncertain:1

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 06, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM3, PP1, PP4, PP5 -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKHD1 p.Ile3177Thr variant was identified in 10 of 974 proband chromosomes (frequency: 0.01) from individuals or families with ARPKD (Bergmann 2005, Denamur 2010, Furu 2004, Gunay-Aygun 2010, Losekoot 2005, Rosetti 2003).The variant was also identified in dbSNP (ID: rs200511261), Clinvitae database (as pathogenic by Emory genetics) RWTH AAachen University ARPKD database (as pathogenic) and PKHD1-LOVD. This variant was identified in the NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles (freq. 0.0001) and Exome Aggregation Consortium database (March 14, 2016) in 5 of 66720 chromosomes (freq. 7.49E-05) in the European population, this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Ile3177 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The case studies by Arbeiter (2008) and Denamur (2010) identify this mutation along with evolutionarily highly conserved missense change c.2414CT (p.Pro805Leu) in patients who died perinatally from ARPKD. In addition, several studies found the variant in patients with severe perinatally-fatal phenotype of ARPKD (Bergmann 2005, Furu 2004, Gunay-Aygun 2010, Rosetti 2003, Losekoot 2005). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Mar 22, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31980526, 30507656, 19940839, 30595564, 15698423, 12846734, 15108281, 18503009, 30650191, 16133180, 19914852, 15108277, 12874454) -

Polycystic kidney disease 4 Pathogenic:3

Feb 24, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 10, 2021

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This PKHD1 variant (rs200511261) is rare (<0.1%) in a large population dataset (gnomAD: 13/250878 total alleles; 0.005%; no homozygotes) and has an entry in ClinVar. It has been observed on the opposite chromosome from other pathogenic variants in individuals affected with PKD4. Two bioinformatics tools queried predict that p.Ile3177Thr would be tolerated, while another predicts it would be damaging. The isoleucine residue at this position is partially conserved across the vertebrate species assessed; some species have a valine substitution at this position. This variant is not predicted to affect normal exon 58 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.9530T>C to be likely pathogenic. -

Mar 27, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive polycystic kidney disease Pathogenic:2 Uncertain:1

Jan 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

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 3177 of the PKHD1 protein (p.Ile3177Thr). This variant is present in population databases (rs200511261, gnomAD 0.01%). This missense change has been observed in individual(s) with polycystic kidney disease on the same chromosome with another PKHD1 variant (p.Pro805Leu)(PMID: 16133180, 15108281, 18503009, 19940839). The haplotype (Pro805Leu; Ile3177Thr) has been observed on the opposite chromosome from other pathogenic variants in an individuals affected with polycystic kidney disease (PMID: 12846734, 15108281, Invitae). ClinVar contains an entry for this variant (Variation ID: 377018). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Biliary tract abnormality Uncertain:1

Apr 28, 2020

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PKHD1-related disorder Uncertain:1

Mar 13, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKHD1 c.9530T>C variant is predicted to result in the amino acid substitution p.Ile3177Thr. This variant has been reported in several patients with polycystic kidney disease. In the majority of patients, it was detected in combination with the PKHD1 variant c.2414C>T (p.Pro805Leu) (Rossetti et al. 2003. PubMed ID: 12846734; Shuster et al. 2019. PubMed ID: 30650191; Bergmann et al. 2004. PubMed ID: 15108281; Denamur et al. 2010. PubMed ID: 19940839; PreventionGenetics). In at least four of these patients familial testing confirmed these variants were inherited as a haplotype (in cis) on the same allele (c.[2414C>T;9530T>C] p.[Pro805Leu;Ile3177Thr]), and this haplotype was in trans with a second PKHD1 variant allele (Rossetti et al. 2003. PubMed ID: 12846734 ; Shuster. 2019. PubMed ID: 30650191; Bergmann et al. 2004. PubMed ID: 15108281). However, the c.9530T>C (p.Ile3177Thr) variant has also been reported in individuals with polycystic kidney disease without p.Pro805Leu (Rossetti et al. 2003. PubMed ID: 12846734; PreventionGenetics). In one case, it was shown to be in trans with the suspected pathogenic variant c.2269A>C (p.Ile757Leu) (Rossetti et al. 2003. PubMed ID: 12846734). The c.9530T>C (p.Ile3177Thr) variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51612884-A-G). In conclusion, the haplotype c.[2414C>T;9530T>C] p.[Pro805Leu;Ile3177Thr] is considered to be pathogenic; however, the contribution of each variant is unknown. Although we suspect the c.9530T>C (p.Ile3177Thr) variant may be pathogenic, at this time the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	T;.
Eigen	Benign	0.075
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		6.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.28	B;B
Vest4		0.52
MVP		0.93
MPC		0.22
ClinPred		0.29	T
GERP RS		5.9
Varity_R		0.21
gMVP		0.51
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200511261; hg19: chr6-51612884;