VCV000477627.15 - ClinVar

NM_000297.4(PKD2):c.203dup (p.Ala69fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000297.4(PKD2):c.203dup (p.Ala69fs)

Variation ID: 477627 Accession: VCV000477627.15

Type and length

Duplication, 1 bp

Location

Cytogenetic: 4q22.1 4: 88007930-88007931 (GRCh38) [ NCBI UCSC ] 4: 88929082-88929083 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 26, 2018	Oct 8, 2024	Nov 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000297.4:c.203dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000288.1:p.Ala69fs	frameshift
NM_000297.3:c.203dupC
NR_156488.2:n.302dup		non-coding transcript variant
NC_000004.12:g.88007936dup
NC_000004.11:g.88929088dup
NG_008604.1:g.5269dup

... more HGVS ... less HGVS

Protein change

A69fs

Other names

Canonical SPDI

NC_000004.12:88007930:CCCCCC:CCCCCCC

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA658657390 OMIM: 173910.0007 dbSNP: rs1187336837 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PKD2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	842	1075
LOC129992813	-	-	-	GRCh38	-	211

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Autosomal dominant polycystic kidney disease	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 20, 2023	RCV000555382.9
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 8, 2022	RCV000681716.7
Polycystic kidney disease 2	Pathogenic (2)	criteria provided, single submitter	Jan 24, 2022	RCV002289770.3
PKD2-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 15, 2024	RCV004752949.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Autosomal dominant polycystic kidney disease Affected status: yes Allele origin: germline	Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research Accession: SCV001430257.1 First in ClinVar: Aug 21, 2020 Last updated: Aug 21, 2020	Clinical Features: Multiple renal cysts (present) , Renal cyst (present)
Pathogenic (Jan 21, 2021)	criteria provided, single submitter (Athena Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001879470.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Publications: PubMed (4) PubMed: 10411676‚ 22508176‚ 29633482‚ 18837007 Comment: This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). … (more) This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as 198insC. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. (less)
Pathogenic (Jan 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Polycystic kidney disease 2 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580810.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PS4_MOD, PM2_SUP	Number of individuals with the variant: 1 Sex: female
Pathogenic (Feb 08, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001801842.3 First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023	Comment: 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 … (more) 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22508176, 10411676, 14993477, 18837007, 29633482, 33437033, 34101167) (less)
Pathogenic (Nov 20, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autosomal dominant polycystic kidney disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000658971.5 First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 17582161‚ 22863349‚ 10411676‚ 18837007‚ 22508176 Comment: This sequence change creates a premature translational stop signal (p.Ala69Glyfs23) in the PKD2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Ala69Glyfs23) in the PKD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKD2 are known to be pathogenic (PMID: 17582161, 22863349). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal dominant polycystic kidney disease (PMID: 10411676, 18837007, 22508176). This variant is also known as 198insC. ClinVar contains an entry for this variant (Variation ID: 477627). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 01, 1999)	no assertion criteria provided Method: literature only	POLYCYSTIC KIDNEY DISEASE 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000034729.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 29, 2017	Publications: PubMed (1) PubMed: 9949210 Comment on evidence: In 7 of 21 cysts from both kidneys of a patient with polycystic kidney disease (PKD2; 613095), Koptides et al. (1999) identified a C insertion … (more) In 7 of 21 cysts from both kidneys of a patient with polycystic kidney disease (PKD2; 613095), Koptides et al. (1999) identified a C insertion within the inherited wildtype PKD2 allele. This C insertion was different from the one previously identified (693insC; 173910.0004) in this family as the germline mutation. The insertion occurred within a sequence of 6 consecutive cytosines (nucleotides 197-203), encoding amino acids 66-68. The authors were unable to determine exactly where the insertion of the cytosine occurred. The mutation was expected to create a translation frameshift, leading to the incorporation of 22 novel amino acids before reaching a stop codon. A polymorphism at nucleotide 83, which was occupied by either G or C, encoding either arginine or proline, enabled Koptides et al. (1999) to verify that the C insertion had occurred in the inherited wildtype allele. (less)
Pathogenic (Sep 16, 2018)	no assertion criteria provided (ACMG Guidelines, 2015) Method: research	not provided Affected status: yes Allele origin: germline	Gharavi Laboratory, Columbia University Accession: SCV000809169.1 First in ClinVar: Oct 01, 2018 Last updated: Oct 01, 2018
Pathogenic (Jul 15, 2024)	no assertion criteria provided Method: clinical testing	PKD2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005363563.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The PKD2 c.203dupC variant is predicted to result in a frameshift and premature protein termination (p.Ala69Glyfs23). This variant was reported in individuals with polycystic kidney … (more) The PKD2 c.203dupC variant is predicted to result in a frameshift and premature protein termination (p.Ala69Glyfs23). This variant was reported in individuals with polycystic kidney disease (see for example, Zhang et al. 2018. PubMed ID: 29633482; Groopman et al. 2019. PubMed ID: 30586318, Table S7). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in PKD2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)

Comment:

This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as 198insC. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene.

Comment:

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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22508176, 10411676, 14993477, 18837007, 29633482, 33437033, 34101167)

Comment:

This sequence change creates a premature translational stop signal (p.Ala69Glyfs*23) in the PKD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKD2 are known to be pathogenic (PMID: 17582161, 22863349). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal dominant polycystic kidney disease (PMID: 10411676, 18837007, 22508176). This variant is also known as 198insC. ClinVar contains an entry for this variant (Variation ID: 477627). For these reasons, this variant has been classified as Pathogenic.

Comment:

The PKD2 c.203dupC variant is predicted to result in a frameshift and premature protein termination (p.Ala69Glyfs*23). This variant was reported in individuals with polycystic kidney disease (see for example, Zhang et al. 2018. PubMed ID: 29633482; Groopman et al. 2019. PubMed ID: 30586318, Table S7). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in PKD2 are expected to be pathogenic. This variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Identification of novel mutations and risk assessment of Han Chinese patients with autosomal dominant polycystic kidney disease.	Zhang M	Nephrology (Carlton, Vic.)	2019	PMID: 29633482
Clinical utility of PKD2 mutation testing in a polycystic kidney disease cohort attending a specialist nephrology out-patient clinic.	Robinson C	BMC nephrology	2012	PMID: 22863349
Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients.	Audrézet MP	Human mutation	2012	PMID: 22508176
Novel method for genomic analysis of PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease.	Tan YC	Human mutation	2009	PMID: 18837007
Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease.	Rossetti S	Journal of the American Society of Nephrology : JASN	2007	PMID: 17582161
Seven novel mutations of the PKD2 gene in families with autosomal dominant polycystic kidney disease.	Torra R	Kidney international	1999	PMID: 10411676
Germinal and somatic mutations in the PKD2 gene of renal cysts in autosomal dominant polycystic kidney disease.	Koptides M	Human molecular genetics	1999	PMID: 9949210

Text-mined citations for rs1187336837 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000297.4(PKD2):c.203dup (p.Ala69fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1187336837 ...