NM_001009944.3(PKD1):c.12061C>T (p.Arg4021Ter) AND Polycystic kidney disease, adult type

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jul 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:: RCV001251463.9

Allele description [Variation Report for NM_001009944.3(PKD1):c.12061C>T (p.Arg4021Ter)]

NM_001009944.3(PKD1):c.12061C>T (p.Arg4021Ter)

Gene:

PKD1:polycystin 1, transient receptor potential channel interacting [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_001009944.3(PKD1):c.12061C>T (p.Arg4021Ter)

HGVS:

NC_000016.10:g.2090751G>A
NG_005895.1:g.46446G>A
NG_008617.1:g.52470C>T
NM_000296.4:c.12058C>T
NM_001009944.3:c.12061C>TMANE SELECT
NP_000287.4:p.Arg4020Ter
NP_001009944.3:p.Arg4021Ter
LRG_487:g.46446G>A
NC_000016.9:g.2140752G>A
NM_001009944.2:c.12061C>T

Protein change:

R4020*

Links:

dbSNP: rs764431330

NCBI 1000 Genomes Browser:

rs764431330

Molecular consequence:

NM_000296.4:c.12058C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001009944.3:c.12061C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Polycystic kidney disease, adult type (PKD1)
Synonyms:: Polycystic Kidney, Autosomal Dominant; POLYCYSTIC KIDNEY DISEASE, ADULT, TYPE I; Polycystic kidney disease 1; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008263; MedGen: C3149841; OMIM: 173900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001425156	Molecular Biology Laboratory, Fundació Puigvert - KidneyPanel_2020	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2020)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 33532864
SCV001427163	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 12, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002558710	(GEEPAD) Grupo de Estudio de la Enfermedad Poliquística Autosómica Dominante, Hospitales Universitarios Virgen de las Nieves y San Cecilio (Granada)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002573077	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 8911610, 25741868
SCV005184295	Juno Genomics, Hangzhou Juno Genomics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 19, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8911610, 29633482, 22185115, 8649614, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing, research

Citations

PubMed

Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players.

Domingo-Gallego A, Pybus M, Bullich G, Furlano M, Ejarque-Vila L, Lorente-Grandoso L, Ruiz P, Fraga G, López González M, Piñero-Fernández JA, Rodríguez-Peña L, Llano-Rivas I, Sáez R, Bujons-Tur A, Ariceta G, Guirado L, Torra R, Ars E.

Nephrol Dial Transplant. 2022 Mar 25;37(4):687-696. doi: 10.1093/ndt/gfab019.

PubMed [citation]

PMID:: 33532864

Autosomal dominant polycystic kidney disease (ADPKD) in an Italian family carrying a novel nonsense mutation and two missense changes in exons 44 and 45 of the PKD1 Gene.

Rossetti S, Bresin E, Restagno G, Carbonara A, Corrà S, De Prisco O, Pignatti PF, Turco AE.

Am J Med Genet. 1996 Oct 16;65(2):155-9.

PubMed [citation]

PMID:: 8911610

See all PubMed Citations (6)

Details of each submission

From Molecular Biology Laboratory, Fundació Puigvert - KidneyPanel_2020, SCV001425156.1

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

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV001427163.2

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

Description

A heterozygous nonsense variant, NM_001009944.2(PKD1):c.12061C>T, has been identified in exon 44 of 46 of the PKD1 gene. The variant is predicted to result in a premature stop codon at position 4021 of the protein (NP_001009944.2(PKD1):p.(Arg4021*)), likely resulting in loss of protein function through truncation, which includes the PKD channel domain (Rossetti, S. et al., 1996). However, loss of function via NMD has not been excluded. The variant is absent in population databases (gnomAD, dbSNP, 1000G), however, it has been reported in at least three patients with kidney cysts and been shown to segregate with disease (Rossetti, S. et al., 1996). In addition, other heterozygous truncating variants located downstream have been reported as pathogenic in individuals with this condition (ClinVar). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.

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

From (GEEPAD) Grupo de Estudio de la Enfermedad Poliquística Autosómica Dominante, Hospitales Universitarios Virgen de las Nieves y San Cecilio (Granada), SCV002558710.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From 3billion, SCV002573077.1

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

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000636627 / PMID: 8911610 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Juno Genomics, Hangzhou Juno Genomics, Inc, SCV005184295.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

PM2_Supporting+PVS1+PS4_Moderate

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

Last Updated: Sep 16, 2024

ClinVar

Relating variation to medicine