6-51903601-A-T

Variant names:

• chr6-51903601-A-T
• rs200179145
• NM_138694.4:c.6992T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_138694.4(PKHD1):​c.6992T>A​(p.Ile2331Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000457 in 1,610,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 3.71

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-51903601-A-T is Pathogenic according to our data. Variant chr6-51903601-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51903601-A-T is described in Lovd as [Pathogenic]. Variant chr6-51903601-A-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.12714306). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.6992T>A	p.Ile2331Lys	missense_variant	Exon 43 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.6992T>A	p.Ile2331Lys	missense_variant	Exon 43 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.6992T>A	p.Ile2331Lys	missense_variant	Exon 43 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 62 AN: 152028 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.00311

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000458 AC: 115 AN: 251278 Hom.: 0 AF XY: 0.000457 AC XY: 62 AN XY: 135806

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: 0.00314

Gnomad NFE exome AF: 0.000405

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000462 AC: 674 AN: 1458008 Hom.: 0 Cov.: 29 AF XY: 0.000469 AC XY: 340 AN XY: 725472

Gnomad4 AFR exome AF: 0.0000600

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: 0.00399

Gnomad4 NFE exome AF: 0.000401

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000408 AC: 62 AN: 152028 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74268

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000288 Hom.: 0

Bravo AF: 0.000174

ExAC AF: 0.000329 AC: 40

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:7

Aug 31, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 06, 2025

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 lysine, which is basic and polar, at codon 2331 of the PKHD1 protein (p.Ile2331Lys). This variant is present in population databases (rs200179145, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 11919560, 12506140, 15698423, 15805161, 19914852, 26673778). 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: 188813). Invitae Evidence 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 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. -

Jun 06, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Feb 01, 2020

Molecular Biology Laboratory, Fundació Puigvert

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKHD1 c.6992T>A (p.Ile2331Lys) missense variant has been reported in four studies in which it is found in a total of 11 patients with autosomal recessive polycystic kidney disease, all in a compound heterozygous state, at least three of whom carried a frameshift variant on the second allele (Ward et al. 2002; Bergmann et al. 2005; Sharp et al. 2005; Gunay-Aygun et al. 2010). Segregation with disease has been shown in at least two studies (Ward et al. 2002; Bergmann et al. 2005). The p.Ile2331Lys variant was absent from 500 controls and is reported at a frequency of 0.00287 in the European (Finnish) population in the Exome Aggregation Consortium. 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. -

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKHD1 c.6992T>A (p.Ile2331Lys) results in a non-conservative amino acid change located in the Right handed beta helix domain (IPR039448) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 251478 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease (0.00046 vs 0.0071), allowing no conclusion about variant significance. c.6992T>A has been reported in the literature in multiple compound heterozygous individuals affected with Polycystic Kidney and Hepatic Disease (Ward_2002, Bergmann_2003, Bergmann_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Polycystic kidney disease 4 Pathogenic:7

Aug 21, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM3_VSTR,PM1,PM2_SUP -

Apr 04, 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 lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (134 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2, v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated right handed beta helix (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic and pathogenic, and reported in compound heterozygous individuals with milder renal disease and autosomal recessive polycystic kidney disease (ClinVar, PMID: 33532864, PMID: 15698423). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate in four affected pairs of siblings (PMID: 15698423). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_Strong, PM1 -

Oct 06, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM2, PP2, PP3, PP5 -

not provided Pathogenic:4

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKHD1: PM3:Very Strong, PM1, PM2, BP4 -

Jun 03, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12846734, 15805161, 12874454, 29956005, 14741187, 20413436, 16523049, 19914852, 15698423, 11919560, 15108277, 12506140, 15706593, 26673778, 29935118, 31980526, 27535533, 31589614) -

Mar 02, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 27, 2018

Eurofins Ntd Llc (ga)

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: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKHD1 p.Ile2331Lys variant was identified in 15 of 836 proband chromosomes (frequency: 0.018) from individuals or families with ARPKD, and was not identified in 200 control chromosomes from healthy individuals (Adeva 2006, Bergmann 2005, Furu 2004, Gunay-Aygun 2010, Sharp 2005). The variant was also identified in dbSNP (ID: rs200179145) as “With likely pathogenic allele”, Clinvitae database (likely pathogenic by ClinVar), the ClinVar database (likely pathogenic by Counsyl), RWTH AAachen University ARPKD database (pathogenic) and PKHD1-LOVD. This variant was identified in the Exome Aggregation Consortium database (March 14, 2016) in 40 of 121394 chromosomes (freq. 0.0003) in the following populations: European in 21 of 66734 chromosomes (freq. 0.0003), Finish in 19 of 6614 chromosomes (freq. 0.003) and not identified in African, East Asian, Latino, South Asian or Other population. The p.Ile2331 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 2 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. In the case study by Adeva (2006) the variant was identified with a truncating mutation in an infant with respiratory distress and hyperechogenic liver and kidneys with intrahepatic bile duct dilatation, the variant was classified as definitely pathogenic. Two ARPKD studies classified the variant as pathogenic (Sharp 2005) and probably pathogenic (Gunay-Aygun 2010) by in silico and segregation analysis. In addition, Bergmann (2005) and Furu (2004) suggest the variant in combination with truncating mutation has a rather moderate effect and associated with minor renal disease. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

PKHD1-related disorder Pathogenic:1

Aug 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKHD1 c.6992T>A variant is predicted to result in the amino acid substitution p.Ile2331Lys. This variant has been repeatedly reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) (see for example, Ward et al. 2002. PubMed ID: 11919560; Bergmann et al. 2003. PubMed ID: 12506140). This variant is reported in 0.31% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Uncertain	0.75	D;.
Eigen	Benign	-0.013
Eigen_PC	Benign	-0.064
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.74	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.019	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.94	P;P
Vest4		0.73
MVP		0.99
MPC		0.43
ClinPred		0.24	T
GERP RS		5.9
Varity_R		0.53
gMVP		0.95

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: rs200179145; hg19: chr6-51768399;