VCV000096383.35 - ClinVar

NM_138694.4(PKHD1):c.2027C>G (p.Pro676Arg)

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.

(13)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_138694.4(PKHD1):c.2027C>G (p.Pro676Arg)

Variation ID: 96383 Accession: VCV000096383.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p12.2 6: 52053189 (GRCh38) [ NCBI UCSC ] 6: 51917987 (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	Mar 29, 2015	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_138694.4:c.2027C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_619639.3:p.Pro676Arg	missense
NM_170724.3:c.2027C>G	NP_733842.2:p.Pro676Arg	missense
NC_000006.12:g.52053189G>C
NC_000006.11:g.51917987G>C
NG_008753.1:g.39437C>G

... more HGVS ... less HGVS

Protein change

P676R

Other names

Canonical SPDI

NC_000006.12:52053188:G:C

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.

0.00799 (C)

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

Exome Aggregation Consortium (ExAC) 0.00220

The Genome Aggregation Database (gnomAD) 0.00681

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00684

Trans-Omics for Precision Medicine (TOPMed) 0.00689

1000 Genomes Project 0.00799

1000 Genomes Project 30x 0.00874

Links

dbSNP: rs115045643 ClinGen: CA149496 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.
PKHD1		-	-	GRCh38 GRCh37	5038	5253

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.
not specified	Benign (3)	criteria provided, multiple submitters, no conflicts	Apr 15, 2013	RCV000082533.24
Autosomal recessive polycystic kidney disease	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000169044.28
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Apr 1, 2020	RCV000224258.15
Polycystic kidney disease 4	Likely benign (1)	criteria provided, single submitter	Apr 6, 2022	RCV002505006.8

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.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000315782.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Apr 15, 2013)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000114575.8 First in ClinVar: Jan 17, 2014 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PKHD1 Number of individuals with the variant: 2 Sex: mixed
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Polycystic kidney disease 4 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001137147.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autosomal recessive polycystic kidney disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000291327.9 First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024
Likely Benign (Oct 29, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281335.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016	Comment: Converted during submission to Likely benign.
Likely benign (Apr 26, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000699854.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016	Publications: PubMed (3) PubMed: 24984783‚ 15698423‚ 21228398 Comment: Variant summary: Variant affects a non-conserved nucleotide a results in a replacement of a medium size and hydrophobic Proline (P) with a large size and … (more) Variant summary: Variant affects a non-conserved nucleotide a results in a replacement of a medium size and hydrophobic Proline (P) with a large size and basic Arginine (R). in silico tools predict the variant to be normal; however these predictions have yet to be confirmed by functional studies. The variant was observed predominantly in the African subcohorts of the ExAC project at an allele frequency of 2.3% (including 3 homozygotes) which exceeds ~3 times the maximal expected allele frequency of a disease causing PKHD1 allele (0.7%) indicating the variant to be in the neutral spectrum. The variant was reported in two autosomal-recessive polycystic kidney disease patients in compound heterozygosity with a potentially pathogenic PKHD1 variant. Clinical laboratories classify variant as Benign/Likely benign via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as Likely Benign. (less)
Likely benign (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Polycystic kidney disease 4 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001325524.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 15698423 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Mar 27, 2014)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: literature only	Polycystic kidney disease, infantile type (Autosomal recessive inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000220202.2 First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022	Publications: PubMed (2) PubMed: 21228398‚ 15698423
Likely benign (Apr 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Polycystic kidney disease 4 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002797232.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Apr 01, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000520871.6 First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 20981092, 21228398, 15698423, 27884173)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005226149.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Jun 30, 2017)	no assertion criteria provided Method: clinical testing	Autosomal recessive polycystic kidney disease Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002081047.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Benign (Aug 26, 2022)	no assertion criteria provided Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV003839869.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023
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Comment:

Variant summary: Variant affects a non-conserved nucleotide a results in a replacement of a medium size and hydrophobic Proline (P) with a large size and basic Arginine (R). in silico tools predict the variant to be normal; however these predictions have yet to be confirmed by functional studies. The variant was observed predominantly in the African subcohorts of the ExAC project at an allele frequency of 2.3% (including 3 homozygotes) which exceeds ~3 times the maximal expected allele frequency of a disease causing PKHD1 allele (0.7%) indicating the variant to be in the neutral spectrum. The variant was reported in two autosomal-recessive polycystic kidney disease patients in compound heterozygosity with a potentially pathogenic PKHD1 variant. Clinical laboratories classify variant as Benign/Likely benign via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as Likely Benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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
Intragenic motifs regulate the transcriptional complexity of Pkhd1/PKHD1.	Boddu R	Journal of molecular medicine (Berlin, Germany)	2014	PMID: 24984783
Carrier testing for severe childhood recessive diseases by next-generation sequencing.	Bell CJ	Science translational medicine	2011	PMID: 21228398
Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD).	Bergmann C	Kidney international	2005	PMID: 15698423
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PKHD1	-	-	-	-

Text-mined citations for rs115045643 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_138694.4(PKHD1):c.2027C>G (p.Pro676Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs115045643 ...