rs200511261

Positions:

• chr6-51748086-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 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:8 U:3
• Conservation: PhyloP100: 6.10

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 Uncertain_significance. Variant got 5 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, 4 uncertain in NM_138694.4
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 377018.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=2, Pathogenic=2}. Variant chr6-51748086-A-G is described in Lovd as [Pathogenic]. Variant chr6-51748086-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.9530T>C	p.Ile3177Thr	missense_variant	58/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.9530T>C	p.Ile3177Thr	missense_variant	58/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.9530T>C	p.Ile3177Thr	missense_variant	58/61	5		A2

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

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 250878 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135538

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: 0.00

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

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.0000331

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

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: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000807 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:8 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2021	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 25, 2019	PM2, PM3, PP1, PP4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 06, 2017	- -
Uncertain significance, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Autosomal recessive polycystic kidney disease Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	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. -

Polycystic kidney disease 4 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 10, 2021	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 24, 2024	- -

PKHD1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2023

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
MutationTaster	Benign	0.82	N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs200511261; hg19: chr6-51612884;