rs746838237

Positions:

• chr6-51959882-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_138694.4(PKHD1):​c.5895_5896insA​(p.Leu1966ThrfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,612,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: PKHD1 NM_138694.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: -5.29

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-51959882-G-GT is Pathogenic according to our data. Variant chr6-51959882-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 167486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.5895_5896insA	p.Leu1966ThrfsTer4	frameshift_variant	36/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.5895_5896insA	p.Leu1966ThrfsTer4	frameshift_variant	36/67	1	NM_138694.4	ENSP00000360158	P2
PKHD1	ENST00000340994.4	c.5895_5896insA	p.Leu1966ThrfsTer4	frameshift_variant	36/61	5		ENSP00000341097	A2

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000757 AC: 19 AN: 251106 Hom.: 0 AF XY: 0.0000884 AC XY: 12 AN XY: 135708

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

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: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000147 AC: 215 AN: 1460894 Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 108 AN XY: 726788

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000179

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: 0.000176

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 152000 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74244

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.000131

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: 0.00813 Hom.: 29

Bravo AF: 0.0000756

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change creates a premature translational stop signal (p.Leu1966Thrfs*4) in the PKHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). This variant is present in population databases (rs746838237, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 15108281, 19940839, 24162162, 27225849). This variant is also known as 5896insA and 5895_5896insA. ClinVar contains an entry for this variant (Variation ID: 167486). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_138694.3(PKHD1):c.5895dupA(L1966Tfs*4) is classified as pathogenic in the context of PKHD1-related autosomal recessive polycystic kidney disease. Sources cited for classification include the following: PMID 19940839, 15698423, 15805161, 12846734, 12506140 and 11919560. Classification of NM_138694.3(PKHD1):c.5895dupA(L1966Tfs*4) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Molecular Genetics, Children's Memorial Health Institute	Sep 25, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 02, 2018	Variant summary: PKHD1 c.5895dupA (p.Leu1966ThrfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.9319C>T, p.Arg3107X; c.9689delA, p.Asp3230fsX34; c.10637delT, p.Val3546fsX22). The variant allele was found at a frequency of 8.3e-05 in 276786 control chromosomes, which is lower than the maximum expected allele frequency for a pathogenic variant in this gene. c.5895dupA has been reported in the literature in multiple individuals affected with Polycystic Kidney and Hepatic Disease and is a common pathogenic variant. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Polycystic kidney disease 4 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 12, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	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) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (23 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported in many patients with polycystic kidney disease (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic in ClinVar. It has also been reported in multiple individuals with autosomal recessive polycystic kidney disease (PMID:15805161) (SP) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Oct 13, 2020	ACMG codes:PVS1, PM2, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Jan 05, 2021	This variant was previously reported in patients of different ethnic origin diagnosed with autosomal recessive polycystic kidney disease and was classified as pathogenic. The variant was previously reported as most frequent or recurrent mutation in the context of polycystic kidney disease in the literature. [PMID: 15108281, 19940839, 24162162, 27225849, 26695994]. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 14, 2024	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 05, 2016	- -
Pathogenic, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26695994, 15108281, 11919560, 27225849, 24162162, 32574212, 30595564, 33282801, 31589614, 19940839) -

PKHD1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 02, 2024

The PKHD1 c.5895dupA variant is predicted to result in a frameshift and premature protein termination (p.Leu1966Thrfs*4). This variant has been repeatedly reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) (see examples: Ward et al. 2002. PubMed ID: 11919560, reported as c.5896insA; Table S2, Denamur et al. 2009. PubMed ID: 19940839; Table 3, Obeidova et al. 2020. PubMed ID: 32574212; Table S2, Domingo-Gallego et al. 2022. PubMed ID: 33532864). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD and has been consistently interpreted as pathogenic in the ClinVar database by other laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/167486/). Frameshift variants in PKHD1 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs746838237; hg19: chr6-51824680;