NM_138694.4(PKHD1):c.9718C>T (p.Arg3240Ter) AND Autosomal recessive polycystic kidney disease

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 18, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000411085.7

Allele description [Variation Report for NM_138694.4(PKHD1):c.9718C>T (p.Arg3240Ter)]

NM_138694.4(PKHD1):c.9718C>T (p.Arg3240Ter)

Gene:

PKHD1:PKHD1 ciliary IPT domain containing fibrocystin/polyductin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p12.3

Genomic location:

Preferred name:

NM_138694.4(PKHD1):c.9718C>T (p.Arg3240Ter)

HGVS:

NC_000006.12:g.51747898G>A
NG_008753.1:g.344728C>T
NM_138694.4:c.9718C>TMANE SELECT
NM_170724.3:c.9718C>T
NP_619639.3:p.Arg3240Ter
NP_733842.2:p.Arg3240Ter
NC_000006.11:g.51612696G>A
NM_138694.3:c.9718C>T

Protein change:

R3240*

Links:

dbSNP: rs1057516577

NCBI 1000 Genomes Browser:

rs1057516577

Molecular consequence:

NM_138694.4:c.9718C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_170724.3:c.9718C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Autosomal recessive polycystic kidney disease (ARPKD)
Synonyms:: POLYCYSTIC KIDNEY AND HEPATIC DISEASE 1; POLYCYSTIC KIDNEY DISEASE, INFANTILE, TYPE I; Polycystic kidney disease, infantile type; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009889; MeSH: D017044; MedGen: C0085548; Orphanet: 731; Orphanet: 8378

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000485896	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Feb 26, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV002051396	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 27, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15698423, 12506140, 30650191, 33940108 Citation Link,
SCV002231366	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 18, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19940839, 12506140, 30650191, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000485896

Counsyl

criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))

Likely pathogenic
(Feb 26, 2016)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

SCV002051396

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Dec 27, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV002231366

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 18, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD).

Bergmann C, Senderek J, Windelen E, Küpper F, Middeldorf I, Schneider F, Dornia C, Rudnik-Schöneborn S, Konrad M, Schmitt CP, Seeman T, Neuhaus TJ, Vester U, Kirfel J, Büttner R, Zerres K; APN (Arbeitsgemeinschaft für Pädiatrische Nephrologie)..

Kidney Int. 2005 Mar;67(3):829-48.

PubMed [citation]

PMID:: 15698423

Refining genotype-phenotype correlations in 304 patients with autosomal recessive polycystic kidney disease and PKHD1 gene variants.

Burgmaier K, Brinker L, Erger F, Beck BB, Benz MR, Bergmann C, Boyer O, Collard L, Dafinger C, Fila M, Kowalewska C, Lange-Sperandio B, Massella L, Mastrangelo A, Mekahli D, Miklaszewska M, Ortiz-Bruechle N, Patzer L, Prikhodina L, Ranchin B, Ranguelov N, Schild R, et al.

Kidney Int. 2021 Sep;100(3):650-659. doi: 10.1016/j.kint.2021.04.019. Epub 2021 Apr 30.

PubMed [citation]

PMID:: 33940108

See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000485896.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002051396.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: PKHD1 c.9718C>T (p.Arg3240X) 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. The variant allele was found at a frequency of 8e-06 in 251230 control chromosomes (gnomAD). c.9718C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney and Hepatic Disease (Bergmann_2003, Bergmann_2005, Shuster_2019, Burgmaier_2021). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002231366.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Arg3240*) 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 (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 12506140, 30650191). ClinVar contains an entry for this variant (Variation ID: 370548). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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