NM_138694.4(PKHD1):c.2725C>T (p.Arg909Ter) AND Autosomal recessive polycystic kidney disease

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 19, 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:: RCV000176696.11

Allele description [Variation Report for NM_138694.4(PKHD1):c.2725C>T (p.Arg909Ter)]

NM_138694.4(PKHD1):c.2725C>T (p.Arg909Ter)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

6p12.2

Genomic location:

Preferred name:

NM_138694.4(PKHD1):c.2725C>T (p.Arg909Ter)

HGVS:

NC_000006.12:g.52043721G>A
NG_008753.1:g.48905C>T
NM_138694.4:c.2725C>TMANE SELECT
NM_170724.3:c.2725C>T
NP_619639.3:p.Arg909Ter
NP_733842.2:p.Arg909Ter
NC_000006.11:g.51908519G>A
NM_138694.3:c.2725C>T
NP_619639.3:p.Arg909*

Protein change:

R909*

Links:

dbSNP: rs727504089

NCBI 1000 Genomes Browser:

rs727504089

Molecular consequence:

NM_138694.4:c.2725C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_170724.3:c.2725C>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
SCV000918010	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 16, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 31730820, 35812281, 34536170, 32574212 Citation Link,
SCV000937061	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19940839, 28492532
SCV001163053	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000918010

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Feb 16, 2023)

germline

clinical testing

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

Citation Link,

SCV000937061

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 19, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001163053

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

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

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

Citations

PubMed

28 novel mutations identified from 33 Chinese patients with cilia-related kidney disorders.

Liang N, Jiang X, Zeng L, Li Z, Liang D, Wu L.

Clin Chim Acta. 2020 Feb;501:207-215. doi: 10.1016/j.cca.2019.10.040. Epub 2019 Nov 13.

PubMed [citation]

PMID:: 31730820

Phenotypic Variability in Siblings With Autosomal Recessive Polycystic Kidney Disease.

Ajiri R, Burgmaier K, Akinci N, Broekaert I, Büscher A, Dursun I, Duzova A, Eid LA, Fila M, Gessner M, Gokce I, Massella L, Mastrangelo A, Miklaszewska M, Prikhodina L, Ranchin B, Ranguelov N, Rus R, Sever L, Thumfart J, Weber LT, Wühl E, et al.

Kidney Int Rep. 2022 Jul;7(7):1643-1652. doi: 10.1016/j.ekir.2022.04.095.

PubMed [citation]

PMID:: 35812281
PMCID:: PMC9263410

See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918010.2

#	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.2725C>T (p.Arg909X) 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 was absent in 251142 control chromosomes (gnomAD). c.2725C>T has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (examples: Liang_2020, Obeidova_2020, Ajiri_2022,Ishiko_2022). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as 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 Invitae, SCV000937061.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Arg909*) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 167491). 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

From Baylor Genetics, SCV001163053.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 19, 2024

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