NM_001009944.3(PKD1):c.8284_8295dup (p.Ile2762_Arg2765dup) AND Polycystic kidney disease, adult type

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Sep 2, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV002052133.4

Allele description [Variation Report for NM_001009944.3(PKD1):c.8284_8295dup (p.Ile2762_Arg2765dup)]

NM_001009944.3(PKD1):c.8284_8295dup (p.Ile2762_Arg2765dup)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_001009944.3(PKD1):c.8284_8295dup (p.Ile2762_Arg2765dup)

HGVS:

NC_000016.10:g.2103772_2103783dup
NG_008617.1:g.39448_39459dup
NM_000296.4:c.8284_8295dup
NM_001009944.3:c.8284_8295dupMANE SELECT
NP_000287.4:p.Ile2762_Arg2765dup
NP_001009944.3:p.Ile2762_Arg2765dup
NC_000016.9:g.2153773_2153784dup
NM_001009944.2:c.8284_8295dup

Links:

dbSNP: rs1596527370

NCBI 1000 Genomes Browser:

rs1596527370

Molecular consequence:

NM_000296.4:c.8284_8295dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_001009944.3:c.8284_8295dup - inframe_insertion - [Sequence Ontology: SO:0001821]

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
SCV002318608	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 22, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11115377, 25741868
SCV002766969	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 2, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11115377, 24611717, 31056860, 25741868
SCV002778263	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 6, 2022)	unknown	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

SCV002318608

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 22, 2022)

germline

clinical testing

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

SCV002766969

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 2, 2022)

germline

clinical testing

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

SCV002778263

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 6, 2022)

unknown

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	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications.

Rossetti S, Strmecki L, Gamble V, Burton S, Sneddon V, Peral B, Roy S, Bakkaloglu A, Komel R, Winearls CG, Harris PC.

Am J Hum Genet. 2001 Jan;68(1):46-63. Epub 2000 Dec 12.

PubMed [citation]

PMID:: 11115377
PMCID:: PMC1234934

A comprehensive search for mutations in the PKD1 and PKD2 in Japanese subjects with autosomal dominant polycystic kidney disease.

Kurashige M, Hanaoka K, Imamura M, Udagawa T, Kawaguchi Y, Hasegawa T, Hosoya T, Yokoo T, Maeda S.

Clin Genet. 2015 Mar;87(3):266-72. doi: 10.1111/cge.12372. Epub 2014 Apr 3.

PubMed [citation]

PMID:: 24611717

See all PubMed Citations (4)

Details of each submission

From 3billion, SCV002318608.1

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

Description

Inframe insertion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. The variant has been reported to be associated with PKD1 related disorder (PMID:11115377). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as uncertain significance 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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002766969.1

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

Description

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 1 (MIM#173900). (I) 0107 - This gene is associated with autosomal dominant disease. Polycystic kidney disease 1 (MIM#173900) is predominantly caused by monoallelic variants, with rare reports of biallelic variants causing disease (OMIM). (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable inframe duplication variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been described once as a VUS in an individual with renal cysts and chronic kidney disease (ClinVar), and reported in four unrelated families with polycystic kidney disease and described as definitely pathogenic (PMID: 11115377, PMID: 24611717, PMID: 31056860, pkdb.mayo.edu). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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 Fulgent Genetics, Fulgent Genetics, SCV002778263.1

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

Last Updated: Feb 4, 2024

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