VCV002444187.4 - ClinVar

NM_138694.4(PKHD1):c.5174G>C (p.Trp1725Ser)

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.

(3)

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/Likely 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_138694.4(PKHD1):c.5174G>C (p.Trp1725Ser)

Variation ID: 2444187 Accession: VCV002444187.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p12.2 6: 52024636 (GRCh38) [ NCBI UCSC ] 6: 51889434 (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 18, 2023	Jun 17, 2024	Jan 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_138694.4:c.5174G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_619639.3:p.Trp1725Ser	missense
NM_170724.3:c.5174G>C	NP_733842.2:p.Trp1725Ser	missense
NC_000006.12:g.52024636C>G
NC_000006.11:g.51889434C>G
NG_008753.1:g.67990G>C
NG_084191.1:g.687C>G

... more HGVS ... less HGVS

Protein change

W1725S

Other names

Canonical SPDI

NC_000006.12:52024635:C:G

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

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.
LOC126859690	-	-	-	GRCh38	-	203
PKHD1		-	-	GRCh38 GRCh37	5054	5269

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.
Polycystic kidney disease 4	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 17, 2024	RCV003152985.3
Autosomal recessive polycystic kidney disease	Likely pathogenic (1)	criteria provided, single submitter	Jan 8, 2024	RCV003611631.2

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.
Likely pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Polycystic kidney disease 4 Affected status: yes Allele origin: unknown	3billion Accession: SCV003841616.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 32901917 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Protein truncation variants are a common disease-causing … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PKHD1-related disorder (PMID: 32901917). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Nephrocalcinosis (present)
Likely pathogenic (Jan 08, 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: SCV004516484.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 32901917‚ 34536170 Comment: This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1725 of the PKHD1 protein … (more) This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1725 of the PKHD1 protein (p.Trp1725Ser). This variant is present in population databases (rs761046498, gnomAD 0.01%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 32901917, 34536170). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2444187). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Pathogenic (Jan 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Polycystic kidney disease 4 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004202251.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PKHD1-related disorder (PMID: 32901917). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1725 of the PKHD1 protein (p.Trp1725Ser). This variant is present in population databases (rs761046498, gnomAD 0.01%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 32901917, 34536170). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2444187). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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
Clinical features of autosomal recessive polycystic kidney disease in the Japanese population and analysis of splicing in PKHD1 gene for determination of phenotypes.	Ishiko S	Clinical and experimental nephrology	2022	PMID: 34536170
Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE.	Seo GH	Clinical genetics	2020	PMID: 32901917

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_138694.4(PKHD1):c.5174G>C (p.Trp1725Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...